Human Reproduction vol.11 no.5 pp.939-94O, 1996
OPINION
Genetic and non-genetic determinants of the human sex
ratio at birth
William H James
The Galton Laboratory, University College London, Wolfson
House, 4 Stephenson Way, London NW1 2HE, UK
I should like to raise two main points in connection with the
recent note by Bernstein (1995). Firstly, the possible genetic
control of human sex ratio and secondly, the variances of the
distributions of the combinations of the sexes in human
sibships and in litters of polytocous mammals.
Possible genetic control of human sex ratio
Bernstein's suggestion that there is some genetic control of
sex ratio is supported by the evidence that some parental HLA
genes may partially control offspring sex ratios.
Ivanyi et al (1972) reported that in the mouse 'a genetic
factor identical with, or closely linked to, the H-2 system is
involved in the control of sex hormone metabolism'. On the
basis of this, they made a remarkable prediction: 'If the
situation in histocompatibility genetics and associated traits in
man is analogous with that seen in the mouse, a great number
of physiological characters and disorders may be expected to
display a statistically significant association with HL-A types'.
The prediction was confirmed the following year when it was
discovered that HLA B 27 is very powerfully associated with
ankylosing spondylitis (Brewerton et al, 1973a) and with
Reiter's syndrome (Brewerton et al, 1973b). Later, Gerencer
et al. (1982) and Oilier et al. (1989) demonstrated variation
in testosterone concentrations by HLA Class 1 alleles in,
respectively, women and men.
Of interest are the facts that: (i) some HLA-associated
diseases (e.g. those associated with B 27) are much more
common in men; (ii) others (e.g. those associated with B 8)
are more common in women; (iii) HLA B 27 is apparently
associated with high testosterone concentrations in men (James,
1991a); (iv) HLA B 8 is associated with low testosterone
concentrations in women (Gerencer et al, 1982).
On the basis of these four points, I suggested that HLA B
27-associated diseases are partially caused by high concentrations of testosterone, and HLA B 8-associated diseases by low
concentrations of testosterone (James, 1991a). There is a large
quantity of data suggesting that high parental concentrations
of testosterone at time of conception are associated with the
subsequent births of boys, and low parental concentrations
with the subsequent births of girls (James, 19%). Hence, I
suggest that the reported excess of brothers of probands
© European Society for Human Reproduction and Embryology
with ankylosing spondylitis, and of sisters of probands with
rheumatoid arthritis constitute support for the notion that the
diseases are partially hormonally caused (James, 1991b).
Further confirmation of these excesses of brothers and sisters
have been supplied by Calin et al. (1993), Deighton et al.
(1993) and Ploski et al (1994).
In short, there is a network of fact and argument tending to
suggest that some of the HLA genes, by controlling hormone
concentrations, not only operate as markers for disease, but
partially (and weakly) control the probability of producing
a boy.
Variances of the distributions of the combinations of the
sexes in human sibships and in litters of polytocous
mammals
Bernstein (1995) wrote: 'James (1994, 1995) claimed that the
subnormal dispersion of sexes within mammalian Utters is due
to the fact that not all zygotes are formed at the same time
during the heat period. But the distribution of sexes in human
sibships is also subnormal (Bernstein, 1952), i.e. a later-bom
sibling is more likely to have the same sex as its older siblings.
This has nothing to do with when fertilization in his or her
mother has taken place during her fertile period'.
There is an error here. The variance of the distributions of
the combinations of the sexes in human sibships is not
subnormal: it is supernormal (e.g. Edwards, 1958). In other
words, as contrasted with binomial expectation, there are
excesses of unisexual sibships, as Bernstein (1952) herself
reported. In contrast, the variance of the distributions of the
combinations of the sexes within litters of some polytocous
mammals is subnormal e.g. the sheep (James, 1976) and the
rabbit, the mouse and particularly the pig (James, 1975). In
other words, as contrasted with binomial expectation, there
are deficits of unisexual litters.
Explanations of these phenomena may be offered. The data
on human sibships would be (partially) explained by the
genetic mechanisms invoked above. Other causes of such
variation are suggested by non-genetic associations with the
sex ratio (James, 1990).
The subnormal variance in mammalian litters is less easily
explained. The distinguished Italian statistician Gini (1951)
commented that such data 'furnishes the unique example so
far known of subnormal dispersion in a statistical series'.
Edwards (1960) noted the theoretical possibility that if the
zygotes in a litter had different probabilities of being male,
such a result might occur. Bearing in mind the evidence (cited
939
W-HJames
in James, 1995) that: (i) the zygotes in mammalian litters are
not formed simultaneously and (ii) the probability P (that a
zygote will be male) varies across the interval during which
zygotes are being formed, it seems that the conditions for
Edwards' (1960) solution are met.
More recently (on the assumption that Edwards' solution is
the correct one), mathematical modelling has been used to
study P (Brooks et al., 1991). This study suggests that P has
a U-shaped distribution across time during the interval that
zygotes are being formed in the pig. This is similar to that
suggested in man by Guerrero (1974) and Harlap (1979). It
will be interesting to see whether experimental confirmation
in the pig can be found for this suggestion of Brooks et al.
(1991).
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