A STUDY OF CERTAIN ASPECTS OF HUMAN GENETICS INCLUDING CONSANGUINITY AND GENETIC DISORDERS IN HUMAN POPULATION OF DG KHAN

Abstract

The consanguineous marriages are strongly favored in many human populations but their prevalence and structure vary depending on culture, religion, and socioeconomic conditions of respective population. These marriages are reported as the leading cause of enhancing the prevalence of autosomal recessive genetic disorders. The challenge of genetic disorders’ burden in the population calls for the development of prevention programs. But the strategies for their implementation require the information about types and prevalence of genetic disorders and family system in population. These achievements are possible by thorough understanding of the determinants of human population genetic structure that is mainly determined by the marriage pattern. Furthermore, the pattern of close marriages in population along with other factors leads to develop the isolated groups having typically confined, well- documented, extended and multigenerational pedigrees. The extended pedigrees with rare disorders are used by geneticists for their linkage studies. Present study focuses on consanguinity and genetic disorders in the population of District Dera Ghazi Khan, Punjab, Pakistan because of its unique geographical location and population structure. The district Dera Ghazi Khan is situated in the center of Pakistan, bounded on the North by Dera Ismail Khan District of N.W.F.P; on the West by Musa Khel and Barkhan districts of Baluchistan, on the South by Rajan Pur, and on the East by river Indus that separates it from all other districts of Punjab province. The population of Dera Ghazi Khan is mainly a tri-ethnic mixture of Baloch, Natives (Non-Baloch) and Indian Migrants (Muhajirs). Social and cultural activities vary in the area but marriages are mostly endogamous within caste or tribes. The harsh and adverse environmental condition restricts the movement of people that result in development of extended families /founder population. The present study showed 70.52% endogamous marriages in the general population and 71.62%, 69.62%, and 70.42% in Baloch, Migrant, and Native populations, respectively. Furthermore high rate of consanguinity (53.57%) with 0.0301 mean coefficient of inbreeding was observed in general population. The first-cousin marriages were found more prevalent. The results were also discussed on the bases of educational status, occupation, and socioeconomic condition and a strong link with these factors wasobserved. Furthermore, statistically significant effect of consanguinity on pregnancy loss (miscarriages, abortions, prenatal deaths), and perinatal deaths (still births, birth of dead child and early neonatal deaths) were found. In addition, the effect of marriage types on specific group of genetic disorders like skin disorders (Albinism, EDs, Alopecia, Aposthia, etc), non-syndromic deafness, and thalassemia were also studied. Five families (A, B, C, D, and E) clinically showed the presence of abnormal nails and skin. In the affected individuals, nychodystrophy of fingernails and toenails started at the same time but differentially lead to anonychia on toenails and onycholysis on fingernails. The skin was abnormal, which bruises and blisters easily. The affected individuals of these skin families showed abnormally high sweating, missing finger-prints and palmoplantar keratoderma. Two families (F, G) exhibited typical features of congenital alopecia including absence of hair on the scalp, axillae, pubic, and other parts of the body. In Family F, linkage was established to hair loss locus on chromosome 8p21. Sequence analysis of HR gene revealed a single base pair deletion mutation at position 431(431delC) in exon 2, leading to frameshifts and premature termination codon 68 bp downstream in the same exon. In family G, genotyping with microsatellite markers failed to detect linkage to any of the known alopecia / ED locus. In three families (H, I, J) affected individuals had pre-lingual, severe to profound hearing loss, with no associated abnormality. The mode of inheritance of the hearing loss was autosomal recessive. Analysis of the genotypes revealed the linkage of the family H to the DFNB35 on chromosome 14, family I, to the locus DFNB44 on chromosome 7, and family J to the DFNB1 locus on chromosome 13. In family J, sequence analysis of the coding exon of GJB2 gene led to the identification of a G-to-A substitution at nucleotide position 71, resulting in a premature stop codon (W24X). For studying the spectrum of β-thalassemia mutations in the population, 164 β- thalassemia chromosomes obtained from 82 different families were analyzed and nine different mutations [IVS I-5, FSC8/9, FSC-5 (-CT), IVS-I-1(G-T), CD41/42 (-TTCT), IVS-II-848 (C-A) and CD 15 (G-A), CD16 (-C) and CD30 (G-C)] in the β-globin gene were detected. Interestingly, frequencies of these mutations vary among different ethnic groups as well as castes/ tribes.