Molecular and Genetic Medicine

Population stratification and its influence on genetic association studies is a controversial topic. Although it has been suggested that stratification is unlikely to bias the results of association studies conducted in developed countries, convincing contrary empirical evidence has been published. However, it is in populations where historical ethnic, religious and language barriers exist that community subdivisions will predictably exert greatest genetic effect, and influence the organization of association studies. In many of the populations of the Indian sub-continent, these basic population divisions are compounded by a strict tradition of intracommunity marriage and by marriage between close biological relatives. Data on the very significant levels of genetic diversity that characterize the populations of India and Pakistan, with some 50,000-60,000 caste and non-caste communities in India, and average first cousin marriage rates of 40%-50% in Pakistan, are presented and discussed. Under these circumstances, failure to explicitly control for caste/biraderi membership and the presence of consanguinity could seriously jeopardize, and may totally invalidate, the results of association/case control studies and clinical trials

Mutations of SLC4A1 (AE1) encoding the kidney anion (Cl-/HCO3 -) exchanger 1 (kAE1 or band 3) can result in either autosomal dominant (AD) or autosomal recessive (AR) distal renal tubular acidosis (dRTA). The molecular mechanisms associated with SLC4A1 mutations resulting in these different modes of inheritance are now being unveiled using transfected cell systems. The dominant mutants kAE1 R589H, R901X and S613F, which have normal or insignificant changes in anion transport function, exhibit intracellular retention with endoplasmic reticulum (ER) localization in cultured non-polarized and polarized cells, while the dominant mutants kAE1 R901X and G609R are mis-targeted to apical membrane in addition to the basolateral membrane in cultured polarized cells. A dominant-negative effect is likely responsible for the dominant disease because heterodimers of kAE1 mutants and the wild-type protein are intracellularly retained. The recessive mutants kAE1 G701D and S773P however exhibit distinct trafficking defects. The kAE1 G701D mutant is retained in the Golgi apparatus, while the mis-folded kAE1 S773P, which is impaired in ER exit and is degraded by proteosome, can only partially be delivered to the basolateral membrane of the polarized cells. In contrast to the dominant mutant kAE1, heterodimers of the recessive mutant kAE1 and wild-type kAE1 are able to traffic to the plasma membrane. The wild-type kAE1 thus exhibits a ‘dominant-positive effect’ relative to the recessive mutant kAE1 because it can rescue the mutant proteins from intracellular retention to be expressed at the cell surface. Consequently, homozygous or compound heterozygous recessive mutations are required for presentation of the disease phenotype. Future work using animal models of dRTA will provide additional insight into the pathophysiology of this disease.

The Y-chromosome is responsible for sex determination in mammals, which is triggered by the expression of the SRY gene, a testis-determining factor. This particular gene, as well as other genes related to male fertility, are located in the non-recombining portion of the Y (NRY), a specific region that encompasses 95% of the human Y-chromosome. The other 5% is composed of the pseudo-autosomal regions (PARs) at the tips of Yp and Yq, a X-chromosome homologous region used during male meiosis for the correct pairing of sexual chromosomes. Despite of the large size of the human NRY (about 60 Mb), only a few active genes are found in this region, most of which are related to fertility. Recently, several male fertility dysfunctions were associated to microdeletions by STS mapping. Now that the complete genetic map of the human Y-chromosome is available, the role of particular NRY genes in fertility dysfunctions is being investigated. Besides, along with the description of several nucleotide and structural variations in the Y-chromosome, the association between phenotype and genotype is being addressed more precisely. Particularly, several research groups are investigating the association between Y-chromosome types and susceptibility to certain male dysfunctions in different population backgrounds. New insights on the role of the Y-chromosome and maleness are being envisaged by this approach