6. The role of sex in heredity
6.1. X-linked inheritance
The fact that in humans females are homogametic and males are heterogametic makes the interpretation of both types of X-linked inheritance patterns difficult. Because women have two X chromosomes, they may be homo- or heterozygous for an X-linked trait / disease. Those women whose heterozygosity is proven by pedigree analysis and / or genotyping, are called obligate heterozygotes (conductors), while those who are only presumptive heterozygotes based on the family tree (i.e. they have no affected offspring, but have affected brothers) are called facultative heterozygotes.
In contrast, men have only one X chromosome therefore they are hemizygous, so they are either affected or carriers when the X chromosome is mutated, or healthy, if a normal (non-mutant) X chromosome is present. As for X-linked disorders 1/3 of the affected males are new mutation carriers! After all, the hemizygous males have reproductive disadvantage since the trait or disease is always manifested in them so the mutant gene is selected out from the population. In women, X chromosome inactivation further complicates the picture: depending on the X inactivation the phenotype can be quite varied - mild or severe - in heterozygotes.
6.1.1. X-linked dominant (XD) Inheritance
In this case, the pedigree pattern is similar to the autosomal dominant, but the two sexes are affected differently.
The main features of this type of inheritance are:
1/ vertical family tree
2/ twice as many women affected as men, 2 : 1 female : male ratio
3/ 50% of the offspring of an affected women - regardless of their sex – are sick 4/ all daughters of an affected man are affected while all sons are healthy (the
father always gives his X chromosome to his daughters, the Y to his sons!)
5/ symptoms of the affected women are often milder and more variable than that of the affected men
While the symptoms of homozygous dominant XAXA females are alleviated only by the X inactivation, whereas in heterozygous XAXa women the product (protein) coded by the normal allele Xa can do the same it as well.
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Traits / diseases determined by genes on the X chromosomal PAR1 region e.g. the Xg blood group antigen and amelogenesis imperfecta (incomplete teeth enamel production) have such inheritance. In the latter one the enamel layer of the teeth is missing and such teeth grow carious more easily.
The most known X-linked dominant disorder is the hypophosphataemia (formerly called vitamin D-resistant rickets, coded on the long arm of the X chromosome), which is characterized by growth retardation in childhood, rickets and low serum phosphate level. It is a treatable disease by large doses of vitamin D and phosphate!
The fragile X syndrome, a trinucleotide (CGG) repeat mutation caused disease is also X-linked dominant. This is the most common cause of male mental retardations. While the normal repeat number is <30, this number is between 200 and 2000 in the affected individuals. Between about 50 and 200 repeats there is the so-called premutation or gray zone. The adult affected males are characterized with a long face, protruding ears, large jaws and large testes. In addition to mental retardation, behavioral problems and mood swings are part of the symptoms. The protein encoded by the FMR1 gene probably causes the symptoms by binding the mRNAs of other genes involved in the functions of the nervous system.
The assessment of the X-linked dominant pedigrees is complicated by the so-called X-linked male lethality. Since there is no normal allele the hemizygous, male embryos already die in utero. In this case, there are usually not as many offspring in the family to realize the 2:1 female : male sex ratio characteristic of such inheritance. Incontinentia pigmenti associated with hemizygous lethality is a disorder of pigmentation characterized by blistering of the skin in early childhood and with partial hair loss that manifests only in women. Rett syndrome, which is basically a neural developmental disorder, is also characterized by male lethality but moreover epigenetic phenomena are involved as well. In girls the typical progressive symptoms of loss of speech and acquired motor functions, the compulsive hand-wringing, ataxia and seizures are due to the mutation of the methyl-cytosine binding protein coding MECP2 gene.
6.1.2. X-linked recessive (XR) Inheritance
To date, more than 400 traits with such inheritance pattern are identified. This value is much greater than that would be estimated on the basis of the number of human genes per chromosome and this fact is due to the easier detection and identification of such traits because of the specific male inheritance pattern derived from heterogametic sex.
Amongst such traits / diseases there are relatively harmless, with mild symptoms such as red-green color blindness, others with severe symptoms such as hemophilia, and lethal as Duchenne muscular dystrophy.
The characteristics of X-linked recessive inheritance are:
1/ zigzag or knight’s move pattern: the disease is transferred from mother to son and from son to his daughter
2/ there are many more men affected than women
3/ sick women are born to affected father and obligate heterozygote mother
4/ affected man usually comes from healthy parents where the mother is obligate carrier
5/ there is no man-to-man transmission
Although hemophilia is known for at least 4,000 years - as already mentioned in the Talmud that in families where one of the sons of the matrilineal relatives died due to bleeding out at circumcision as a result, their newborn sons were not circumcised - the first point mutation was described only in 1986. The X-linked recessive hemophilia has two forms: Hemophilia A, which is due to the failure of blood clotting factor VIII, and hemophilia B, which is due to the failure of blood clotting factor IX.
In 40% of hemophilia A cases a specific mutation of the factor VIII gene occurs. The intron 22 of the gene contains two small genes of unknown function, the F8A and F8B.
About 400 kb away there are more copies of F8A of as well. Among these copies intrachromosomal crossing over takes place during meiosis, causing the inversion of the corresponding chromosome piece and thus factor VIII gene falls apart into two distant pieces.
This is the cause of the lack of clotting factors and hemophilia. The most common mutation causing hemophilia occurs in the paternal germ line during meiosis. The large number of divisions and the concominant increased spontaneous mutation rate typical to paternal gametogenesis explain among other things that mutations occur with higher probability in the offspring of aged fathers.
One of the best known and most studied cytoskeletal diseases is Duchenne muscular dystrophy. This X-linked recessive disease, which was described in the second half of the 19th century, begins with difficulties of standing up in the 2nd-3rd years of life - Gower's sign - and associated with increasing muscle weakness.
The boys around the age of 10 are wheelchair-bound then die around 20 years of age. Because the disease is relatively common (incidence of 1:3500), and to this day is incurable, it is clear that it is intensively investigated. Thus came to light that the cause of the disease is a gene mutation affecting a cytoskeletal protein called dystrophin. The dystrophin, a muscle cell specific protein whose C-terminal end is bound to the sarcolemma through a glycoprotein complex of six components and the N-terminus linked to the actin cytoskeleton. The dystrophin is the product of the largest currently known gene, which is 2400 kb in length, and thus its transcription takes more than 16 hours. The function of dystrophin in muscle is the cell membrane stabilization. The mutation is often a frame-shift causing deletion, and thus the cell does not produce dystrophin, or a protein with completely altered structure and function is synthesized. If only an in-frame mutation occurs in the dystrophin gene, that is only a small part is deleted, then the so-called Becker muscular dystrophy with milder symptoms is formed. The Duchenne and Becker muscular dystrophies are due to different mutant alleles of the same gene, so they are examples of allelic heterogeneity as well. As many other mutations (for example, point mutations, and duplications) occur in the dystrophin gene, multiplex allelism is also typical for it.
Since the affected men generally do not reach reproductive age, they can not transmit their mutant gene to the offspring, so this sub-lethal mutant gene should gradually disappear from the population. However, the incidence of the disease is fairly constant; it is just possible as the rate of new mutations is high, that the mutant gene is repeatedly produced. According to new observations deletion mutations involving the dystrophin gene take place typically in the maternal germ line while the other types of mutations are rather common in the paternal germ line, but the reason has not been known yet.
The X chromosome inactivation further complicates the pedigree analysis also in X-linked recessive inheritance. The phenotype of heterozygous females varies depending
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on the ratio of healthy XA and mutant Xa bearing cells. If the gene product is a soluble protein, such as the clotting factors in hemophilia, the effect is “averaged”. In other words, these women are asymptomatic but biochemically will be different from normal. However, where the product is localized to a given cell type, there the symptoms appear in a mosaic form. Such as the hypohydrotic ectodermal dysplasia, where the mutation causes the absence of sweat glands and the abnormal development or deficiency of dentition.