Articles in PresS. Physiol Genomics (August 18, 2015). doi:10.1152/physiolgenomics.00074.2015
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Chromosome Y genetic variants: impact in animal models and on human disease
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J.W. Prokop1, C.F. Deschepper2
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HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806 USA
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Institut de recherches cliniques de Montréal (IRCM) and Université de Montréal, Montreal (QC)
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Canada H2W 1R7
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Abbreviated title: Chromosome Y in human, mouse, and rat
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To whom correspondence should be addressed:
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Christian F. Deschepper,
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Institut de recherches cliniques de Montréal (IRCM)
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110 Pine Ave West
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Montréal (QC) Canada H2W 1R7
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E-mail: [email protected] ….
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Copyright © 2015 by the American Physiological Society.
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Abstract
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Chromosome Y (chrY) variation has been associated with many complex diseases ranging from
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cancer to cardiovascular disorders. Functional roles of chrY genes outside of testes are suggested by
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the fact that they are broadly expressed in many other tissues and correspond to regulators of basic
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cellular functions (such as transcription, translation and protein stability). However, the unique genetic
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properties of chrY (including the lack of meiotic crossover and the presence of numerous highly
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repetitive sequences) have made the identification of causal variants very difficult. Despite the prior
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lack of reliable sequences and/or data on genetic polymorphisms, earlier studies with animal chrY
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consomic strains have made it possible to narrow down the phenotypic contributions of chrY. Some
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of the evidence so far indicates that chrY gene variants associate with regulatory changes in the
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expression of other autosomal genes, in part via epigenetic effects. In humans, a limited number of
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studies have shown associations between chrY haplotypes and disease traits. However, recent
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sequencing efforts have made it possible to greatly increase the identification of genetic variants on
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chrY, which promises that future association of chrY with disease traits will be further refined.
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Continuing studies (both in humans and in animal models) will be critical to help explain the many sex
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biased disease states in human which are not only contributed to by the classical sex steroid
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hormones, but also by chrY genetics.
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Keywords
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Chromosome Y, consomic strains, phenotypic traits, rat, mouse, human disease, sex differences
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Introduction
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In mammals, sex is determined by the complementation of sex chromosomes, such that males are XY
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and females are XX. The mammalian chromosomes X and Y (chrX and chrY) diverged from an
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ancestral autosomal chromosome pair around 300 million years ago due to four sequential events
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(60). The first one is believed to have been the introduction of the sex determining region of ChrY
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(Sry) gene as the locus driving differentiation of gonads into testes, followed by chrY losing the ability
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for most of the chromosome to recombine with chromosome X (chrX). Ultimately, this led to the
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separation of chrY into two distinct domains: 1) the pseudoautosomal region (PAR; 5% in human);
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and 2) the non-pseudoautosomal region (NPAR; 95% in human), also known as the male-specific
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region on chrY (MSY). ChrYPAR allows for mitotic pairing, and constitutes the only part of chrY that is
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able to recombine with the chrX (115). Sry is found on the MSY, along with several additional protein
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coding genes that have homologous counterparts on chrX (115).
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The MSY has features that set it apart from all other chromosomal regions, particularly because the
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lack of recombination. Firstly, there is an elevated rate of mutation in male gametes (45), but since
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the resulting de novo variants [either single nucleotide variants (SNVs) or insertion-deletions (indels)]
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cannot be removed, they become fixed in the transmission from father to son. Likewise, variants that
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increase fitness cannot be separated from variants that decrease fitness, such that positive selection
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of beneficial traits can result in the maintenance of associated negative traits. Secondly, most
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ancestral genes from the chromosome have been lost on MSY in the course of vertebrate evolution,
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with the only few genes that have been retained showing specialization in either sex determination,
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male fertility, and X/Y dosage compensation (10, 27, 58). Finally, repetitive sequences (such as
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transposable elements) have accumulated in many species, resulting in large heterochromatic
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regions.
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Given the high rate of degeneration of MSY across evolution, some had made the prediction that the
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human MSY might become extinct in around 10 million years (1). In addition to the fact that this
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perspective might have contributed to a relative lack of interest, many experimental hurdles have
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made it difficult to understand whether MSY has broader implications to biologic functions and/or
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disease state. Indeed, without recombination, variants within large population association studies
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cannot be segregated by classical linkage disequilibrium (LD) genetic methods. Therefore, causal
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variants cannot be narrowed down to smaller regions neither by defining LD blocks of variants nor by
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performing congenic mapping in animals. Secondly, knockouts and other targeted mutations are
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difficult to generate, due to the presence of large stretches of repetitive sequence and the fact that
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many MSY genes are required for reproductive success. Thirdly, since large fractions of MSY
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comprise large repeat units (amplicons), often organized as inverted repeats (palindromes), MSY
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sequencing is particularly challenging, especially with short read next generation technologies (8). In
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fact, when certain species’ genomes are sequenced, MSY is either ignored altogether, or the
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corresponding sequence exists as hundreds of independent scaffolds with little to no confidence on
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chromosomal organisation. Unlike the majority of genomic regions that can be reliably sequenced with
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short reads (60-100 base pairs) of next generation sequencing, the sequencing of the MSY is still
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dependent on the generation of bacterial artificial chromosomes (BAC) and/or the use of long read
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sequencing technology (such as PacBio), thus increasing the difficulty and the overall cost of
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sequencing. Finally, in addition to the fact that there is considerable inter-species differences in MSY
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sequences (due to the elevated rate of variation, the process of gene conversion, and the absence of
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segregation of traits), genes on the MSY vary considerably between species both in terms of which
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particular genes have been retained from the ancestral chromosome, or in the expression profiles of
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retained or gained genes in several tissues. Thus, experimental evidence obtained in one vertebrate
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species may not always be readily applicable to another one.
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Nonetheless, data obtained in recent years have shown that MSY genetic variants may contribute to
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phenotypic diversity in traits as varied as cardiovascular functions, immune cell properties, or cancer
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susceptibility, as discussed below. Likewise, investigation in new animal models have, in combination
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with recent sequencing data of MSY in several mammalian species, provided clues concerning
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possible mechanisms whereby MSY could contribute to such diverse phenotypes. In this review, we
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will discuss how the growing body of research is contributing to change our view of MSY contributions
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to complex phenotypic traits.
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1. The contributions of genetic MSY variants to phenotypic traits may segregate from that of
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sex hormones
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One of the prevailing views of mammalian sex determination is that male and female somatic cells are
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initially indifferent, with sexual dimorphisms being imposed by the type of gonads initially developed
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(137). In this view, the Sry gene in mammals initiates testicular development and suppresses ovarian
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differentiation (87)(127). Once the gonads in respective sexes are formed, hormones secreted by the
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gonads (estrogens by the ovary or testosterone by the testes) result in further sex differentiation
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(132)(112). However, there is evidence that sex chromosome complementation (i.e. XX vs. XY) plays
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roles that are independent from that of gonadal steroids. For instance, several reports showed that in
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placental mammals, early XY embryos are more advanced than XX counterparts at gestational times
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that occur before the time of gonadal differentiation (16). Likewise, almost one-third of transcripts in
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bovine blastocyst (including MSY-encoded genes other than Sry in male embryos) show sexual
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dimorphism in their expression levels (11). However, expression of MSY genes may not be the only
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ones responsible for these differences, because inactivation of chrX-linked genes is incomplete in
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blastocysts, so that expression of most corresponding transcripts is up-regulated in female vs. male
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blastocysts (11).
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Outside of initial gonad development, most phenotypic traits with differences between males and
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females are commonly thought to result from differences in circulating estrogen and testosterone
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between the sexes. For example, the increased risk of cardiovascular disease in males is thought to
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be primarily contributed to by the lack of estrogen’s protectiveness in males, thus explaining why risk
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increases in females after -menopause (69). Many reviews have focused on the hormonal
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contributions to sex differences in phenotypic traits for human and animal models
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(95)(96)(129)(80)(67). However, many MSY genes are expressed outside of gonads. In humans, the
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contributions of MSY genes and contributions of protein products are illustrated by the data provided
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by the Human Protein Atlas (126) (Fig. 1). Both in higher primates and rats (but not mice), genes
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such as Sry show a similar pattern of expression across tissues (124), including a high level of
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expression in kidneys (3). Expression of MSY genes in tissues other than male gonads thus
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represent potential for genetic contributions of MSY to sex-dependent differences, and highlight the
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need to elucidate the functions of these genes outside of sex determination and the physiology of
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male gonads.
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Is there evidence that the contributions of sex hormones to phenotypic traits segregate from that of
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sex chromosomes? In humans, the majority of sex reversal disorders (XX males and XY females)
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involve the translocation or mutations of the SRY gene. In such, an XX male commonly has SRY
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translocated to autosomes, whereas an XY male commonly has SRY mutations that perturb the
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function of the protein it encodes for. In XY female athletes, MSY has been suggested to associate
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with stature in an androgen-independent manner (42). While future studies of these patients may
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elucidate the genetics of sex differences in disease susceptibility (82), progress of this field of work is
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greatly limited by the rarity of such subjects.
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By dissociating Sry from MSY in animal models, it has been possible to mimic the sex reversal
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genetics of humans, and thus create XY “gonadal” females and XX “gonadal” males, which provide
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models to study the genetic contributions of sex chromosome in greater detail. In particular, a panel of
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four mouse strains constitutes what is referred to as the model of “four core genotypes”(FCG) (6).
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The panel comprises two types of “gonadal males” [i.e. the wild-type XY males (XYM) and the
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transgenic XX males (XXM)] and two types of gonadal females [i.e. the wild-type XX females (XXF)
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and the Sry-deleted XY females (XYF)]. Comparisons between strains have made it possible to
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differentiate between the effects of “gonadal” vs. that of “chromosomal” sex. For instance, differences
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between XYM and XXM should be due to sex chromosome complementation rather than to
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androgens. Likewise, differences between XXF and XYF should be due sex complementation rather
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than to estrogens.
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Although the FCG model has been used predominantly to show the impact of sex chromosome
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complementation on either behavioral traits or neural functions, the model has also made it possible
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to show that sex complementation affects systems other than the central nervous system (6)(5). For
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instance, in mouse models of autoimmune diseases, XX mice are more affected than XY mice, with
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the difference being irrespective of their type of gonad (116). Likewise, treatment of FCG mice with
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angiotensin II causes different changes in blood pressure in XX vs. XY mice, with the effect of
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chromosomal sex going even in the opposite direction from that of sex steroids (50). Sex
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chromosome complement has also been shown to play a role in the susceptibility to some viral
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infections (99) as well as to several metabolic phenotypes, including adiposity, feeding behavior, fatty
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liver and glucose homeostasis (64).
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Despite the utility of the FCG model, it cannot fully differentiate between the respective influence of
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chrX and chrY. In that model, chrX may be implicated via differences in either: 1) chrX gene dosages
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(in case of incomplete inactivation of chrX genes), 2) chrX gene imprinting (as ChrX genes receive
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different paternal imprints in XX and XY mice); and 3) in chrX allelic mosaicism (present in XX, but not
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in XY animals) (6). However, additional lines of evidence indicate that MSY itself may have an impact
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on a variety of biologic functions, either in humans or in animal models.
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2. Genetic MSY haplotypes and human disease
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In human males, comparison between groups carrying genetic variants of MSY has provided
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evidence implicating MSY more directly in the regulation of biologic processes and disease
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susceptibility. In initial studies, a HindIII restriction fragment polymorphism in the centromeric MSY
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region was shown to associate with either lower blood pressure (35), higher blood pressure (22), or
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higher plasma cholesterol (21) in Caucasian populations. However, these associations were not
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replicated in more recent and well-powered subsequent studies (100)(107)(56). One possible
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explanation may be the existence of multiple stata within a HindIII haplotype, such that a single
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marker does not segregate populations with enough resolution for association studies (100).
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More recently, a system using a panel of binary single nucleotide polymorphisms (SNP) markers has
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made it possible to divide human MSY into a phylogenetic tree containing well-defined haplogroups
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(51). This system also provides investigators with tools to perform more robust association analyses.
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Using such markers in Caucasian British populations, the MSY haplogroup I associated with
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increased risk of coronary artery disease (20). The increased risk was independent of traditional
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cardiovascular risk factors, but associated with differential expression of inflammation and immunity
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related genes in macrophages (20). In HIV-infected humans, the MSY haplogroup I also associated
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with increased morbidity and decreased responses to antiviral therapies (111). In populations of
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African origin, there are SNPs within MSY-encoded TBL1Y and USP9Y genes, with the rs768983
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SNP in the TBL1Y gene defining the MSY E1b1a haplogroup (106)(122). In these populations, the
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most frequent allelic combination of that SNP with another one in USP9Y associates with lower levels
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of triglycerides and higher HDL-cholesterol, and thus with a more favorable lipoprotein pattern (106).
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In Japanese men, the O2b* and O2b1 haplogroups (which are confined to East Asian populations)
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have much lower risk of prostate cancer than other haplogroups (41). Expression analyses of chrY
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genes have also associated MSY genes with neurological phenotypes such as anxiety, ADHD,
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depression and autistic behaviors (104).
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3. Animal models to study MSY associated phenotypic traits
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Several lines of evidence implicating MSY genes in physiology and disease have been obtained using
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animal models (particularly mice and rats). The first suggestions about possible roles of MSY genes
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were derived from comparisons of the progenies of reciprocal F1 crosses between two inbred stains
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(110)(114). As parents in such crosses represent either of the two possible strain combinations,
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differences in their respective progenies suggest a parent-of-origin effect for sex chromosomes.
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Nonetheless, reciprocal F1 hybrids also differ in terms of maternal environment, of ova cytoplasm,
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and in the origin of chrX. Less ambiguous models are those provided by chromosome substitution
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strains (CSS)(also known as “consomic” strains), where one particular chromosome within a host
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strain (A) is substituted by its counterpart from a donor strain (B) (77). MSY consomic strains are
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created by first intercrossing a male from strain B to a female from strain A, and then using the
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resulting F1 males for multiple generations of backcrosses to the host strain A (Fig. 2). This creates
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the consomic strain that shares with its host strain the same: 1) genetic background (including
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chrYPAR, autosomes, chrX, mitochondrial DNA), and 2) pre- and postnatal maternal environment
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(including inoculated microbiota). In the resulting model, the only differences between the consomic
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and the host strains relate to the composition of MSY, thus providing a way to bypass the
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experimental problem resulting from the lack of recombination of MSY. In mouse and rats, nearly all
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studies rely on identifying first sex-dependent differences between two inbred strains, and then
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showing that the differences co-segregate with the MSY in consomic strains, a procedure that
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minimizes the possibility that the MSY-dependent phenotypic differences derive from genetic
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alteration of the MSY in the course of generation of the consomic strains. Phenotyping of consomic
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strains has been performed for a variety of selected phenotypes in either mice or rats (Table 1). More
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recently, larger scale standardized phenotyping efforts have been performed in rats
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(http://pga.mcw.edu).
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Both in rats and mice, MSY variants were found to impact on a large variety of phenotypes, and
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several possible mechanisms have been tested to account for these differences. In mice, the genetic
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contribution of MSY represent a particular situation: although classical mouse laboratory inbred
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strains are overwhelmingly derived from M. m. domesticus (of European origin), MSY is derived from
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M.m. musculus (of Asian origin) for most strains (78)(12). It was therefore hypothesized that some
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effects of MSY may relate to the subspecies origin of MSY in mouse, and this possibility was tested
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using models where MSY from a large number of donor strains were introgressed into one particular
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host strain (120)(18). In one study, MSY from M.m. musculus associated with significantly lower
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plasma HDL-cholesterol levels than in strains carrying MSY from M. m. domesticus (120). In contrast,
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associations co-segregating with the MSY sub-species origin were not found as a possible
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explanation for some immune-related phenotypes (18).
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Interestingly, MSY-dependent phenotypes in mouse often appear to relate to several aspects of
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androgen biology, including adult plasma testosterone levels (52)(14)(121)(17) or the effects of either
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post-pubertal (52)(74)(66) or perinatal testosterone (89) on several organs. In the course of evolution,
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where genes are usually selected on the basis of their advantage for the survival of the species, it
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makes evolutionary sense that the father-related transmission of MSY variants could relate with
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androgen-related biology. Indeed, evolutionary advantages of variants transmitted through the
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paternal cell line are bound to concern preferentially male-related biologic features, which includes the
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production of androgens and/or their biologic effects (45). Of note, the effects of sex steroid
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hormones fall in two categories: 1) the organizational effects (which are permanent and occur early in
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development), and 2) the activational effects (which occur after puberty and are transient) (24)(4). In
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essence, the early organizational phase programs the developing organism for how it will respond to
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sex hormones later during adult life. The organizational effects of sex steroids are limited to a
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restricted period of sensitivity called the “critical period of sexual differentiation”. The timing of that
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critical period is species-specific: in rodents, it includes the last two days of gestation and the first
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days of postnatal life (28)(133). In all mammals studied to date, there is an abrupt discharge of
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testosterone in the first few hours after birth (26). Postnatal testosterone appears to have actions that
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are distinct from that of testosterone during gestation (108). Altogether, perinatal testosterone has
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important effects on several aspects of sexual differentiation, as it shapes several behavioral patterns,
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the development of external genitalia, the programing of the adult pattern of secretion of
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gonadotrophins and growth hormone, and several brain neuroanatomical features (132)(129).
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However, it appears that perinatal testosterone may also have long-term consequences on other
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phenotypes, including the rate of body weight increase (9), several metabolic functions
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(79)(76)(31)(101) and the general organization of circadian rhythms (2)(139). In at least one instance,
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the effects of MSY on adult phenotypic traits were found to be a consequence of differential effects of
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testosterone occurring previously at perinatal times. Male C57BL/6J mice differ from their
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C57BL/6J.MSY A/J counterparts as: 1) postpubertal testosterone has hypertrophic effects on adult
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C57BL/6J cardiomyocytes, but not in that from C57BL/6J.MSY A/J mice; and 2) C57BL/6J neonatal
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mice show signs of stronger perinatal androgenization than their C57BL/6J.MSY A/J counterparts (89).
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When the perinatal actions of androgens in developing C57BL/6J mice are prevented by
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administration of flutamide (an androgen antagonist), testosterone no longer exert hypertrophic effects
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on cardiomyocytes later during adult life; conversely, when C57BL/6J.MSYA/J are exposed to higher
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levels of testosterone during the perinatal period, their cardiomyocytes become sensitive to the
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hypertrophic effects of testosterone later during adult life.
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Despite the several studies showing possible roles of androgens in the mediation of the phenotypic
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effects of MSY variants, there are also other studies reporting that these effects may be independent
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from testosterone. One example is that of differences in the concentration of neurotransmitters in
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certain brain areas (14)(121). In another study, MSY variants were found to impact on the mortality
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rate following infection with coxackievirus B3 (CVB3) through the basal levels of invariant natural killer
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T cells and to associate with the severity of experimental allergic encephalitis; both types of effects
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appearing to be independent from differences in testosterone levels (17)(18).
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Since rats provide additional benefits over the mouse for measuring cardiovascular phenotypes,
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studies using rat MSY consomic models have focused primarily on such cardiovascular traits (43).
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Initial studies on the impact of exchange of the MSY between the spontaneously hypertensive rat
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strain (SHR) and the normotensive Wistar-Kyoto (WKY) strain suggested contributions of the MSY to
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blood pressure (39). Similar effects were found when the MSY originated from the SHR stroke prone
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(SHRSP) rat strain (30). Additional studies using MSY consomic models between SHR and the
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Brown Norway (BN) rats (57), the BN and Dahl salt sensitive strain (SS) rats (72), and BN and Fawn-
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hooded hypertensive strain (FHH) rats (71) suggested that something exclusive to the MSY from SHR
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contributes to blood pressure differences between males and females. As in some mouse studies,
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the effects of the MSY from SHR appear to be androgen-dependent, since: 1) its contribution to blood
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pressure is blocked when SHR MSY consomics are crossed with the testicular-feminized rat
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containing a loss of function mutation to androgen receptor (AR) (38); and 2) the timing of the rise of
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testosterone at puberty is altered in SHR MSY consomics (37). Interestingly, the SRY gene has been
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shown to interact directly with AR in humans, thus suggesting one possible mechanism (136).
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Other experiments using rat consomic strains have shown that the effects of MSY variants are not
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limited to strictly cardiovascular traits. For instance, consomic exchange of MSY between the BN and
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SS rat strains suggested that MSY variants could alter kidney functions such as urinary albumin levels
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(72). Likewise, rat MSY consomics also show differences in the concentration of brain
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neurotransmitters, in learning and behavior, and in features of the metabolic syndrome (including
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blood lipids) (57, 118, 124). High-throughput phenotyping protocols were applied to consomic rats
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where the MSY from either SS or FHH rats were introgressed within the BN background
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(http://pga.mcw.edu). About 200 different traits were tested in these models, with results suggesting
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that MSY may contribute to a wide range of phenotypes, including differences in body size, in organ
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size, in the properties of white and red blood cell properties and the amplitudes of vascular responses.
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4. Profiling of expression of MSY genes in tissues suggests functions in organs other than
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testes
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As mentioned previously, the expression of several MSY genes outside of the testis (Fig. 1) indicates
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that they may play roles unrelated to male reproductive functions. Among those genes, the one that
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may have been characterized in greatest detail for its roles outside of testis is Sry. In the brain, Sry
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has been tied to a variety of functions, as reviewed recently (124). In the human digestive system
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(particularly in the colon), SRY is expressed at readily detectable levels and it has been suggested as
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a potential regulator of genes involved in Hirschsprung disease, potentially explaining the 5:1 male to
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female ratio of this disease (65). Likewise, the readily detectable levels of SRY expression in human
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skin may be significant in light of studies showing correlations between SRY expression levels and
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male pattern baldness (23). Interestingly, SRY is also expressed in male pluripotent stem cells being
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induced by reprogramming (102), which is of interest in light of the well-known role of the SRY
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homologous protein SOX2 in pluripotency (70). All of the SOX genes (including SRY) contain a
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structurally homologous HMG domain sequence that binds and regulates DNA, with SRY being most
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similar to the SOXB subgroup that includes SOX1, SOX2, and SOX3 (92). The homology of Sry with
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SoxB genes may also be consistent with the documented functions of Sry in the brain (124), as it may
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overlap with some of the critical functions played by Sox3 (the Sry orthologous gene on chrX) in brain
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development (25). Even in mouse, where expression of Sry is almost non-detectable in tissues other
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than testes, low levels of expression have been found in some brain nuclei, where it may promote
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sexually dimorphic expression of particular genes and yield a genetically “masculinized” brain
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(33)(32)(132).
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Studies comparing the expression profiles of both Sry and Sox3 in rat tissues showed expression of
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Sry (but not of Sox3) within kidneys, a pattern that was further shown to hold true in multiple primates
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(3). Delivery of a Sry expression vector into the kidneys of normotensive rats can elevate blood
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pressure through changes in the sympathetic nervous system (40) and regulatory changes of
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components of the renin-angiotensin system (RAS) (36). The tissue expression profile for Sry
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suggests that it gained a kidney-specific function over Sox3 (3). An additionally duplicated Sry3 gene
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has been found in the SHR rat strain (125). Consomic rats suggest that this duplicated Sry3 contains
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a non-synonymous variant, P131T, that alters regulation of promoters of RAS genes (95). The
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overlap between Sry and Sox3 in their ability to regulate promoters of RAS genes may be pertinent for
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their roles within the brain as well, because RAS genes share with Sox3 the ability to contribute to
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development of the hypothalamic-pituitary-adrenal axis (3). Both the rat Sry and the human SRY
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proteins have similar effects in their abilities to regulate multiple RAS genes (73)(95). Direct binding of
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SRY protein to promoter sequence of RAS genes such as MAS1 has also been shown for human (3).
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Sry is not the only gene on the MSY that may be linked to functions outside of testes. In XYY males,
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expression of the NLGN4Y gene correlates with neurological phenotypes such as anxiety, ADHD,
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depression and autistic behaviors (104). In cancer, a recent review has detailed the potential roles of
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several MSY genes, including TSPY, RBMY, TGIF2LY, VCY, BPY2, DAZ, CDY1, and SRY (55). On
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the basis of network based expression analysis, up to 22 genes on the MSY have been identified as
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being possibly linked to cancers in several tissues, including the prostate (54).
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In C57BL/6J and C57BL/6J.MSY A/J mice, strain-specific differences were found in the cardiac
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expression levels of Uty and Kdm5d, two MSY-encoded genes that both belong to the family of H3
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lysine demethylases (134)(109) and also ubiquitously expressed in humans (Fig. 1). Although
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differences in the expression of these genes were limited in mouse hearts to just the first postnatal
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day, that period corresponds to the time known as the critical period when androgen is believed to
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exert programming effects. Interestingly, UTY in humans was also found to be expressed at lower
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levels in macrophages of men with MSY haplogroup I (which associates with increased risk of
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coronary artery disease) (13).
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In mammals, chrY and chrX evolved from an ancestral pair of autosomes. In humans, only 3% of the
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ancestral genes have been retained on chrY, in comparison to 98% on chrX (10). However, recent
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sequencing efforts of the euchromatic part of MSY across eight mammals has revealed that the genes
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that have resisted decay belong to a group that cannot result from a random selection process. Since
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these genes correspond to ancestral X-Y gene pairs that escape inactivation in females, the surviving
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gene pairs (X-X in females, X-Y in males) appear to be dosage-sensitive regulators. Moreover, these
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genes are expressed in a wide spectrum of tissues, and can be categorized into five overlapping
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functional families, i.e. regulators of chromatin modification, of ubiquitination, of transcription, of
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splicing, and of translation (10). These genes therefore appear to be potentially important regulators
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of a wide range of vital cellular functions in several tissues, which provides possible mechanisms
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whereby MSY gene variants could contribute to many different aspects of health and disease.
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5. MSY variants may regulate autosomal genes via epigenetic chromatin remodeling
366
Several lines of evidence indicate that some of the effects of MSY genes are mediated via changes in
367
chromatin organization. Hearts from both castrated and intact C57BL/6J and C57BL/6J.MSY A/J mice
368
show differences in their transcriptomic profile, along with strain-specific differences in the identity of
369
testosterone-sensitive genes (66). These differences in gene expression are accompanied by strain-
370
specific differences in the distribution of androgen-receptors in cardiac chromatin, with some of the
371
differentially occupied regions matching the loci of differentially responding cardiac genes (89).
372
Differential distribution of androgen receptors is also observed in cardiac chromatin from 1 day-old
373
pups, along with differences in the distribution of accessible chromatin sites and of H3K4me3 marks
374
(which characterize active promoters). Within the genes closest to sites showing differential H3K4
375
trimethylation, functional enrichment was observed for genes related to nucleosome organization
376
and/or regulation of nucleic acids. Other studies using C57BL/6J and C57BL/6J.MSYSJL mice have
377
also documented strain-specific differences in the transcriptomes of CD4+ T cells (18). When
378
differentially expressed genes were tested for enrichment for functional Gene Ontology (GO) terms,
379
many terms were associated with chromatin modification events whose dysregulation may affect gene
380
transcription. MSY was also associated with alternative and differential splicing of genes in both CD4+
381
T cells and macrophages in C57BL/6J and C57BL/6J.MSYSJL male mice (18).
382
383
The above results are compatible with recent results describing the functions of genes retained on the
384
MSY of several vertebrates. The numbers of such genes vary across species, ranging from 17 in
385
humans and only 9 in mice (10). However, 5 out of these 9 genes (Sry, Rbmy, Ube1y, Usp9y and
386
Zfy) have evolved testis-specific expression in mice. The remaining broadly expressed genes are Uty
387
and Kdm5d (involved in the processes of chromatin modification and/or ubiquitination) and Ddx3y and
388
Eif2s3y (involved in the processes of RNA splicing and/or translation). Uty is the counterpart on MSY
389
of the Utx gene on chrX; in mice, encodes proteins that form functional complexes with other factors,
390
and has functions that are partially redundant with those of Utx (61)(113). Despite being part of the H3
16
391
lysine demethylases family, Uty (in contrast to Utx) is devoid of such enzymatic activity, but acts
392
primarily as a recruiter of the H3K4 methyl-transferase complex (113). In addition, UTX and UTY have
393
the ability to regulate the activity of several promoters by association with BRG1 (the ATP-dependent
394
subunit of the chromatin remodeling Swi/Snf complex) (61)(113). BRG1 has also been shown to
395
induce chromatin modifications that allow androgen receptors to bind to their cognate response
396
elements, and is required for effective transcriptional regulation of androgen-regulated genes (29)(63).
397
The data suggesting a role of Uty in MSY-dependent phenotypes in mice might be interesting in light
398
of the fact that in humans, MSY haplogroups show differences in the level of UTY expression in
399
macrophages (13).
400
401
Besides histone demethylases, other data have suggested alternative mechanisms whereby MSY
402
variants may exert their effects via chromatin regulatory factors in mice. By comparing C57BL/6J
403
mice to consomic strains carrying MSY from 11 other inbred strains, Case et al. found that the
404
numbers of copies of the multicopy Sly and Rbmy genes correlated with the severity scores of either
405
EAE or viral myocarditis, as well as with upregulation of genes in immune cells (19). However, neither
406
Rbmy nor Sly are likely to exert their regulatory actions in immune cells via their protein products,
407
because their expression is testis- and germ line-specific. Alternatively, it has been proposed that
408
higher frequencies of multicopy MSY genes may create domains that bind to chromatin remodeling
409
proteins, leading to fewer euchromatic DNA regions and less transcriptional activity by restricting the
410
overall availability of the chromatin remodeling proteins (19)(18). Interestingly, similar mechanisms
411
have recently been proposed for D. melanogaster, where comparison of MSY consomic strains
412
showed that polymorphic MSY associate with quantitative effects on the expression of several
413
hundreds autosomal genes (62)(138). These effects do not appear to be linked to the products of
414
protein-coding genes, but rather to effects of MSY heterochromatin that may sequester chromatin
415
regulatory factors.
416
17
417
The SRY protein is also known to play roles in the remodeling of chromatin architecture. It recruits
418
heterochromatic protein 1 (HP1) to DNA through the most abundant repressor domain in the human
419
genome, KRAB (81). KRAB subsequently recruits the epigenetic regulation complex of KAP1 that
420
includes HP1, DNA methyltransferases, and the NuRD Histone deacetylase complex (49, 85). The
421
physical interaction between SRY and the KRAB domain has been mapped for both proteins (86, 93).
422
Knockdown of KRAB containing proteins decrease some of the pathways needed for testis
423
determination, namely Sox9 (88). Even without the recruitment of the KRAB domain to regions of the
424
genome, following an initial recruitment of KAP1 to genomic regions, epigenetic modifications are
425
maintained for greater than 50 population doublings (7). This suggests a difficult to test hypothesis,
426
where expression of MSY genes such as Sry during early development could epigenetically
427
“masculinize” cells, and where the “masculinized” state is maintained following the removal of
428
expression of the MSY gene.
429
430
6. Sequencing variants in the MSY
431
To expand on previous identification efforts of SNPs that allow the classification of MSY variants into
432
different haplogroups (51), a high-coverage sequencing study was recently performed in a wide range
433
of samples that covers the majority of clades of the phylogeny. These efforts yielded 13,261 high-
434
confidence SNPs, 66% of which were previously unreported (46). When these results were combined
435
to that of five other recent high-coverage sequencing studies, a total of 33,479 potential SNPs were
436
identified (albeit with lower confidence thresholds), and it is anticipated than even higher numbers of
437
SNPs will be identified in the near future (46). These newly discovered SNPs, when applied to
438
populations originating from as many as 128 countries, have allowed for an expansion and redefinition
439
of chrY haplotypes and sub-haplotype groups (83)(131)(96). Mapping SNVs in larger cohorts using
440
next-generation sequencing is becoming more common, allowing for mapping the characteristics of
441
human migration and the discovery of de novo variants (47, 53). Interestingly, some have recently
442
developed a new genotyping technique that combines validated multiplex PCR with Ion Torrent based
443
sequencing of amplified fragments, along with software tools to identify MSY SNPs (96). This
18
444
technique promises to make it possible to genotype simultaneously many more SNPs than what is
445
possible with techniques based on single-based primer extension chemistry, and yields tools to
446
perform efficient high-throughput genotyping for future phenotypic trait association studies.
447
448
The recent sequencing efforts have also be useful to further understand the idiosyncrasies of chrY
449
genetics. For instance, out of the 13,261 high-definition MSY variants recently reported (46), 259
450
result in missense, nonsense, and frame shift mutations within MSY genes (Fig. 1). The frequency
451
distribution of damaging variations in MSY single-copy genes also suggests that purifying selection is
452
ongoing (46), which is in keeping with the findings that the genes conserved from the ancestral
453
chromosome represent in fact a group of highly conserved genes (10). As mentioned previously, the
454
lack of inter-chromosomal recombination impairs the removal of inserted retrotransposed sequences.
455
This has resulted in the occurrence on the MSY of retrotransposed genes such as Med14y in rat (94)
456
and CDY in humans (59). Also, studies have revealed that sequences on the MSY are less static
457
than previously anticipated. For instance, gene conversion is the process of nonreciprocal transfer of
458
sequence without crossover (either within or between chromosomes). Gene conversion events were
459
found to be abundant between arms of palindromes on the MSY (105), as well as between the MSY
460
and chrX (103)(123). In the bovine MSY, conversion has driven massive gene duplications (10), with
461
copy number variants of TSPY in bull (Bos taurus and Bos indicus) being associated with the quality
462
of bull semen (75). Sequencing of the rat MSY (10) revealed duplication of the Sry gene with break
463
points of the gene duplication occurring at LINE elements, which suggests convergence (94).
464
Similarly, other wild caught rat species have undergone Sry duplication independently (15, 68, 94),
465
domestic cats have multiple Sry genes (84), and humans with Turner syndrome or exposure to
466
radiation can undergo SRY gene duplication (90, 91).
467
468
Progress in sequencing of the MSY has also revealed the extent of differences between several
469
species. In particular, the mouse MSY appears to be spectacularly different from humans or other
470
higher primates (117): 1) only 2.2% of the MSY derives from the ancestral autosomes that gave rise
19
471
to the mammalian sex chromosomes; 2) the remaining of the MSY is dominated by acquired
472
amplicons of three protein-coding and rodent specific gene families, comprising 126 Sly, 197 Srsy,
473
and 306 Ssty copies, and 3) in contrast to other species, 99.9% of the mouse MSY is euchromatic.
474
As mentioned above, copy number variation of Sly in the mouse MSY shows linkage to a paternal
475
parent-of-origin effect on autoimmune disease in female offspring (20).
476
477
Of note, sequencing approaches still struggle with identification of indels on chrY, which may be
478
interesting in light of data showing that loss of chrY (LOY) may have impact on cell functions. In
479
prostate cancer, chrY is one of the most frequently lost chromosomes (128). In the PC-3 human
480
prostate cancer cell line (which is devoid of chrY), back-transfer of chrY suppresses the tumorigenicity
481
of these cells, thus suggesting a functional importance of chrY (128). LOY is also an event that
482
occurs frequently in normal hematopoietic cells from elderly men (44). In cancer-free men, it was
483
determined that the median survival times of subjects with LOY were 5.5 times shorter than that of
484
their counterparts without LOY, even after adjustment for common confounders, including age,
485
hypertension, exercise, smoking, diabetes, body mass index, blood lipids profiles and ancestry (44).
486
Likewise, LOY in hematopoietic cells associates with increased risk for non-hematological cancer
487
mortality (44). Interestingly, even smoking has been associated in humans with transient and dose-
488
dependent mutagenic effects of LOY, including the removal of stretches of MSY sequences (34).
489
490
7. The future of MSY research
491
ChrY has long constituted one of the most challenging regions of the mammalian genome. The past
492
several years have seen an expansion of data on chrY, allowing for a better understanding of its
493
evolutionary characteristics, of its sequence variations, and the impact of the latter on disease and
494
complex traits. With the continuing decrease in the cost of genome sequencing, future chrY variants
495
will be identified within the several thousands of genomes that will be sequenced in the coming years.
496
Further resolution of variants will be useful to refine our understanding of how chrY may associate
20
497
with disease traits. Additional future human research will likely focus on somatic mutations, loss of
498
chrY, and the impact of gene convergence.
499
500
The new emerging picture of MSY genes, as evidenced by the fact that they are broadly expressed in
501
many tissues outside of testes and correspond to regulators of processes as fundamental as
502
transcription, translation and protein stability, is that they may have a significant impact on a variety of
503
biologic functions. One of the mechanisms whereby MSY variants may associate with disease traits
504
is that it appears that they may ultimately lead to changes in expression of other autosomal genes.
505
Animal models therefore remain critical for narrowing down such mechanisms. Having reliable
506
sequence for chrY in rodent models will make it possible to genetically modify MSY genes to study
507
disease associations. Future large scale analyses of phenotypic traits in chrY consomic mouse and
508
rat strains may also increase our ability to correlate chrY gene variants to phenotype, and ultimately
509
understand how orthologous genes may drive disease state in humans. One area that has not
510
received much attention yet is the potential involvement of non-coding RNA transcripts originating
511
from chrY, as these genes are likely to play a role in chrY biology.
512
513
Altogether, there is increasing evidence for connections between chrY genetic variation and disease
514
states, as summarized in Fig. 3. Continuing association studies will be critical to help explain the
515
many sex biased disease states in human which are not only contributed to by the classical sex
516
steroid hormones, but also by chrY genetics.
517
518
Grants:
519
J.W.P. was supported by the National Institutes of Health Office of the Director grant K01ES025435.
520
C.F.D. was supported by grant MOP-93583 from the Canadian Institutes of Health Reseach (CIHR).
521
522
523
21
524
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31
889
FIGURE LEGENDS:
890
891
Fig. 1: Expression of MSY genes in human tissues of the Human Protein Atlas RNAseq.
892
Red blocks indicate expression higher than 0.1 RPKM per gene per tissue or presence in
893
immunohisto cytochemistry. Genes colored red are shared between rodents (rat and mouse) and
894
human, including genes identified to be species specific duplication of a single gene in the other
895
species, such as TSPY genes of human. Variants identified in multiple databases are shown to the
896
right. Databases included ClinVar (http://www.ncbi.nlm.nih.gov/clinvar), dbSNP 142 for
897
nonsynonymous (ns) and frameshift (fs) mutations, Catalog of Somatic Mutations in Cancer
898
(COSMIC, http://cancer.sanger.ac.uk/cosmic), and the Human Gene Mutation Database (HGMD,
899
http://www.hgmd.cf.ac.uk/).
900
901
Fig. 2: Generation of ChrY Consomic animals. A male individual from the donor strain is first
902
crossed to a female from the host strain. Resulting F1 males are then backcrossed to a female from
903
the host strain to generate the N2 generation. Males from the latter are backcrossed again to females
904
from the host strain, the procedure being repeated (n) times. The genome of the final consomic strain
905
is the same as that of the host strain, with the exception of the MSY from the donor strain.
906
907
Fig. 3: Summary of diseases that MSY genes have been associated with, and of challenges
908
related to the particular properties of this part of chrY. See text for further detail.
909
910
911
912
913
914
32
915
Table 1: MSY consomic rodent models
916
Species
Host strain(s)
MSY donor
Phenotypes
strain(s)
mouse
PHL
PHH
C57BL/FaSt
PHH / PHL
NZB/BiNJ
CBA/HGnc
Possible MSY
References
genetic variation
Adult plasma testosterone
Sub-species
Jutley et al. (52)
origin
Adult plasma testosterone
Sub-species
Botbol et al. (14)
origin
Tordjmann et al. (121)
C57BL/6J
RF/J
Adult plasma testosterone
n.d.
Case et al. (17)
C57BL/FaSt
CBA/FaSt
Testoterone-dependent
Sub-species
Jutley et al. (52)
weight of seminal vesicle
origin
C57BL/6
AKR
Chemosensory identity
n.d.
Yamazaki et al. (135)
DBA1
C57BL10
Testosterone-dependent
n.d.
Monahan et al. (74)
n.d.
Llamas et al. (66)
n.d.
Praktiknjo et al. (89)
Sub-species
Botbol et al. (14)
origin
Tordjmann et al. (121)
urinary chemosignals
C57BL/6J
A/J
Testosterone-dependent
adult cardiomyocyte size
C57BL/6J
A/J
Perinatal testosterone
exposure
NZB/BiNJ
CBA/HGnc
Brain neurotransmitters
DBA1
C57BL10
Aggressive behavior
n.d.
Monahan et al. (74)
SAL / LAL
LAL / SAL
Hippocampal morphology
n.d.
Hensbroek et al. (48)
DH/Sgn
KK/Ta
Body weight / length
C57BL/6J
SJL
T cell transcriptome /
Copy numbers of
chromatin remodeling genes
Sly and Rbmy
Suto et al. (119)
Case et al. (18)
C57BL/6J
A/J
Cardiac transcriptome
n.d.
Llamas et al. (66)
C57BL/6J
A/J
Autosomal chromatin
n.d.
Praktiknjo et al. (89)
architecture / chromatin
remodeling gens
MF1
RIII
Cell number in blastocysts
deletion
Burgoyne et al. (16)
DH/Sgn
16 inbred
Plasma HDL-cholesterol
Sub-species
Suto et al. (120)
strains
C57BL/6J
12 inbred
strains
origin
EAE / CVB3 myocarditis
Copy number of
Case et al. (17)
Sly and Rbmy
Case et al. (18)
33
genes
rat
WKY/Hsd
SHR/Hsd
Blood pressure /
SHR/Hsd
WKY/Hsd
sympathetic activity /
Sry
Ely et al. (39)
Turner et al. (124)
behavior response
WKY
SHRSP
Blood pressure / metabolic
n.d.
syndrome
917
918
919
920
Davidson et al. (30)
Strahorn et al. (118)
BN
SHR/Hsd
Blood pressure / blood lipids
n.d.
Kren et al. (57)
BN
SS
Urinary Albumin
n.d.
Mattson et al. (72)