Human Reproductive Genetics

Francis Collins, remarks at a press conference on the prediction of the sequencing and analysis of the human genome[1]. After the addition of a 50 cap and poly(A) tail, segments of non-coding mRNA known as introns are excised; mRNA can be spliced in different ways (alternative splicing) to allow a single DNA sequence to code for different proteins [5] (Figure 1.1). During metaphase, the chromosomes line up along the middle pole of the cell (known as the metaphase plate).

In contrast, a polymorphism is a change in the DNA sequence that occurs in at least 1% of the population[6]. It allows the preovulatory follicle to be receptive to the LH surge in the middle of the menstrual cycle. The incidence of variants at the population scale remains one of the best indicators of pathogenicity.

The Yq variant indicates that part of the Y chromosome contains only heterochromatin in the distal long arm (Yqh). Fisher's view of the way discretely inherited genes [called polygenes, because of their (infinitely) large number] determine continuous quantitative phenotypes [25]. In particular, many polymorphisms have been identified in intronic, non-coding regions of the genome [13,44], in sharp contrast to Mendelian diseases [71], but nevertheless consistent with the notion that complex diseases are driven primarily by non-coding DNA variants that putatively signal the involvement of gene regulation [72 74].

Examination of the adult offspring (F2 generation) of prenatally exposed F1 fathers, but not mothers, had higher BMI than in offspring of unexposed F1[108].

FIGURE 1.1 RNA transcription and translation.

Louwers and Joop S.E. Laven

Candidate gene studies are based on the hypothesis that the gene of interest is involved in the pathogenesis of the disease or trait being investigated. Therefore, a potential association of the D19S884 marker in the fibril gene with PCOS was found in Han Chinese women. Two SNPs in the promoter region of the genes encoding CYP17A1 and CYP11A1 were associated with serum androgen levels in a subset of Indian women [14].

In a recent meta-analysis including 12 studies, only one single nucleotide polymorphism (rs9939609) in the FTO gene significantly increased the risk of PCOS in women. A recent meta-analysis found no significant association between INS VNTR polymorphisms and PCOS risk in the general population. Recently, based on the fact that serum levels of anti-Mullerian hormone (AMH) are increased in women with PCOS SNP in.

AMH gene as well as in the AMH Type II Receptor (AMHR2) gene, these genes have been studied. However, no associations were detected between nine more SNPs in the TNF-α gene and the risk for PCOS. However, due to the heterogeneity and low quality of the studies related to PCOS polymorphisms in the meta-analysis, the results should be interpreted with caution according to these authors[23].

The SNP on chromosome 11 in the region of the follicle-stimulating hormone B polypeptide (FSHB) gene was strongly associated with the previous PCOS NIH diagnosis as well as with luteinizing hormone (LH) levels [28]. This may suggest that these genes may be involved in follicular growth arrest as well as in the metabolic disturbances associated with PCOS[36]. Almost 15% of the male genome is involved in male reproduction, but only a handful of genes have been identified as clinically useful in the evaluation of male infertility [5].

The presence or absence of tall stature is thought to relate to the short stature homeobox-containing gene, which resides in the pseudoautosomal region of the X chromosome. Variations in the presence or absence of mature spermatozoa in the testes of men with Klinefelter syndrome are likely related to the associated degree of gonosomal mosaicism. The AZFc subregion is located at the distal end of AZF and appears to be one of the primary drivers of genetic variation in the Y chromosome[43].

TABLE 8.1 Genetic causes of male infertility.

The AZFc region of the Y chromosome: at the crossroads of genetic diversity and male infertility. Frequent polymorphism of mitochondrial DNA polymerase gamma gene (POLG) in patients with normal spermiograms and unexplained subfertility. CAG repeat polymorphism of mitochondrial DNA polymerase gamma gene in Macedonian infertile and fertile men.

Single nucleotide polymorphisms of the gonadotropin-regulated testicular helicase (GRTH) gene may be associated with impaired human spermatogenesis. Some single-nucleotide polymorphisms of the TSSK2 gene may be associated with a defect in human spermatogenesis. Since mitochondria are the main suppliers of energy in the form of ATP, they can be considered powerhouse cells.

Each mitochondrion contains between 1 and 15 copies of mtDNA [33], whereas each nucleoid is thought to consist of 1 to 3 mtDNA molecules[34]. The fusion process ensures the correct functioning of the mitochondria and the distribution of mtDNA molecules throughout the organelle [36]. The morphology of the mitochondria in the cytoplasm of a metaphase II oocyte is different compared to those found in somatic cells.

It should be noted that the fertility of the older animals was reduced compared to the younger animals [66]. Further TE differentiation will result in the formation of the placenta, while the ICM will develop into the embryo proper. Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases.

Mutational dependence of mitochondrial DNA copy number in the first stages of human embryogenesis. Recently, however, additional functions have been ascribed to the decidualized stromal compartment of the endometrium, indicating that the decidua has a key role in TABLE 10.1 Accuracy of recurrent implantation. Mutations in the FSHR gene show different phenotypes depending on the functionality of the protein they confer [61].

The GNAS gene encodes the α subunit of the guanine nucleotide-binding protein (G protein) implicated in the process of signal transduction [108]. ERAL1 protein binds to the mitochondrial 12S rRNA and is involved in the assembly of the small mitochondrial ribosomal subunit.

TABLE 8.2 Epigenetic changes during spermatogenesis.

Ovarioleukodystrophy is a white matter wasting leukoencephalopathy of the central nervous system associated with POI. Pathological variants of three of its subunits (ie, EIF2B2, EIF2B4, and EIF2B5) have been associated with POI associated or not with neurological symptomatology [136]. The Ataxia Telangiectasia Mutated (ATM) gene codes for a protein kinase implicated in cell cycle control, detecting DNA damage known to result in a chromosome breakage disorder.

Pathological mutations in ATM result in ataxia telangiectasia, an AR disease that exhibits cerebellar degeneration, oculomotor dysfunction, immunodeficiency, cancer susceptibility, increased radiation sensitivity and chromosomal instability, and POI [139]. Mutations in BMPR1B have been found to cause skeletal syndrome with absent or hypoplastic ovaries[ 140 ]. Bloom syndrome is an AR disease associated with mutations in the gene encoding the DNA helicase BLM.

The main symptoms of Bloom syndrome include short stature, typical rash on sun-exposed areas, moderate immunodeficiency, increased risk of cancer due to chromosome instability and hypogonadism [141]. WRN encodes another DNA helicase that, when mutated, causes Werner syndrome, a mature progeria with an increased risk of cancer and atrophic gonads [142]. Another POI-related syndromic premature aging is GAPO, caused by recessive mutations in the ANTXR1 gene, whose protein is involved in cell adhesion and migration.

The mutation process is by expansion in each generation depending on several factors (sex, CGG repeat number, the presence of AGG interspersion, external agents and possibly others) [147151]. The level of triplet expansion modifies the methylation pattern, which combined produces changes in FMR1 mRNA size and changes in their translational properties (Table. FMR1 gene escapes physiologically from X-chromosome methylation, but in the fully mutated allele it is methylated and FMR1 expression is sprained [152].

This picture is further complicated by the presence of mosaicism, both in length and methylation, which blurs the boundaries between the phenotypes of the PM and the full mutation [153,154]. A mother will pass the affected allele to 50% of her sons or daughters, while a father will pass it on to all his daughters and none of his sons. In the presence of PM alleles and in some cases of intermediate alleles, in 20% of women and 50% of older men, fragile X-associated premature ovary (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS) appear (Table 11.4).

FMRP expression in these germ cells coincides with the loss of expression of the pluripotency-associated protein [171]. Ovaries are atypical because they age faster than the rest of the organs. In fact, the majority of laboratory testing of POI women consists of karyotype and FMR1 gene testing.

Dynamics of the ovarian reserve and impact of genetic and epidemiological factors on age of menopause. Novel inactivating mutation of the FSH receptor in two siblings of Indian origin with premature ovarian failure. Delayed puberty and primary amenorrhea associated with a novel mutation of the human follicle-stimulating hormone receptor: clinical, histological, and molecular studies.

Epigenetic analysis of critical region I for premature ovarian failure: demonstration of a highly heterochromatic domain on the long arm of the mammalian X chromosome. A novel heterozygous mutation of the AIRE gene in a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal syndrome (APECED). Primary ovarian insufficiency in classic galactosemia: role of FSH dysfunction and timing of lesion.

Physiological functions of the imprinted Gnas locus and its protein variants Gαs and XLαs in human and mouse. A distinct DNA methylation boundary in the 50 upstream sequence of the FMR1 promoter binds nuclear proteins and is lost in fragile X syndrome.