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Introduction
Male infertility, pleiotropic genes, and increased risk of diseases in future
generations
Bruno Dallapiccola
Cattedra di Genetica Medica
Università La Sapienza di Roma
Infertility affects up to 15% of the potentially fertile human population (WHO,
1990). This is in obvious contrast with the genetic program of any individual
which is expected to work towards a peak of efficiency to achieve the
reproduction. Modern individuals are made up of a range of heritable
characteristics, each of which in past generations as found in those ancestors who
generated most descendants (i.e. had the greatest reproductive success). Thus, the
failure of some people to reproduce raises an important question: why have these
people’s genetic programmes, shaped and honed so ruthlessly over past millenia,
failed to translate survival and actions into reproduction?
Two main causes of infertility may be recognized: clinical and behavioural.
Clinical infertility seems high, particularly in western societies. A WHO study in
25 countries and covering more than 10 000 infertile couples showed that tubal
blockage for females and testicular malfunction for males were the main causes in
the majority of definitive diagnoses (WHO, 1990). Most of these causes are
probably the result of past or current infections, or the consequence of exposure to
a wide range of modern environmental pollutants. It is possible that physiological
responses that would have led to reproduction in the past environments now falter
or fail, some individuals never encountering in their life-time the particular
circumstances that in previous generations would have triggered reproduction.
People carrying alleles of particular genes which react in a maladaptive way with
environment will be selected against. Natural selection is therefore active on
people whose reproductive success is below average just as ruthlessly as it has
ever done in the evolutionary past. Male reproductive genes are subjected to a
rapid evolution driven by sexual selection, suggesting a higher mutation rate
(Wyckoff et al., 2000). Infertile people may now have some opportunity to take
advantage of assisted conception techniques and to reproduce. The result may be
the persistence and expansion of lineages which are only adapted to reproduce in
the modern environment. It is therefore mandatory to know the biological effects
of alleles associated to human infertility. Many genes involved in infertility have
“pleiotropic” effects. It is the case of CFTR (see Mastella and Castellani in this
issue), a glycoprotein active in several exocrin glands which is associated with
cystic fibrosis when altered in the structure and in the production. The gene
encoding CFTR is also mutated in about 66% of patients with congenital bilateral
absence of the vas deferens (CBAVD). The reproduction of males carrying CFTR
mutations by MESA/ICSI techniques could raises the risk of offspring with a
(mild or severe) form of cystic fibrosis to 50%. For couples with CBAVD-related
infertility CFTR mutation analysis and genetic counselling of the patient and his
partner is essential before MESA/ICSI procedures are performed. According
Harper (1998), two important questions which need to be asked (but frequently
are not) by those attempting to investigate and treat infertility are:
1. Is the infertility one aspect of a genetic disorder that might be transmitted?
2. Will correction of infertility give an increased risk of malformations in the
offspring?
The genetic causes of male infertility are numerous and involves primarily genes
active in a) failure of germ-cell migration; b) spermatozoan defects; c) germ-cell
maturation impairment. Most of the genes involved in these processes have been
studied in animal models (see articles of Animal models section) by transgenic
experiments. These models have provide biological evidence of the “pleiotropic
nature” of spermatogenic-related genes. Some of them, affects haematopoiesis,
and melanogenesis (c-kit and SCF); germline cell division, oocyte differentiation
and membrane cytoskeleton (Lis1); proteolysis, meiotic control and chromatic
reorganization (ubiquitin-related genes); muscle weakness, atrophy, myotonia and
hypogonadism (DMPK, myotonin protein kinase). Since only limited human
studies are available on these genes, an exact risk value in offspring it is difficult
at present (see Clinical genetic problems with fertility implications). Interestingly,
children born after ICSI procedure are twice as likely to have major congenital
abnormalities as children conceived naturally, as well as an increase risk of
neurodegenerative diseases (i.e. spinal and bulbar muscular atrophy) in future
generations (ISLAT Working Group, 1999; Dowsing et al., 1999). However, the
absence of large scale follow-up studies, give unrealistic any possible conclusion
at present (Hawkins et al., 1999). In any case, biological and clinical consideration
on ICSI hazard are mainly focused on chromosome anomalies and Y-linked
genes. What is the risk for future generations when mutated alleles of male
infertility genes with pleiotropic effects are transmitted the progeny? To answer at
this conundrum, careful and meticulous genetic and epidemiological studies
should be established on parents and children. However, I am confident that this
goal will be reached subsequently to a complete elucidation of the biological role
of all genes active in male reproduction.
WHO (1990) Global estimates for health situation assessment and projections.
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Dowsing A.T., Young E.L., Clark M., McLachlan R.I., de Kretser D.M.,
Trounson A.O. (1999) Linkage between male infertility and trinucleotide repeat
expansion in the androgen-receptor gene. Lancet, 354, 640-643.
Hawkins M.M., Barratt C.L.R., Sutcliffe A.G., Cooke I.D. (1999) Male infertility
and increased risk of diseases in future generations. Lancet, 354, 1906-1907.
ISLAT Working Group (1999) ART into Science: Regulation of Fertility
Techniques. Science, 281, 651-653.
Harper P.S. (1998) Practical Genetic Counselling. Butterworth Heinemann,
Oxford.
Wyckoff G.J., Wannnng W., Wu CI (2000) Rapid evolution of male reproductive
genes in the descent of man. Nature, 403, 304-306.