Genetic variation and haplotype structures of innate immunity genes in eastern India

Bairagya, Bijan B.; Bhattacharya, Paramita; Bhattacharya, Sujit; Dey, Uposoma; Ghosh, Trina; Maiti, Sujit; Majumder, Partha P.; Mishra, Kankadeb; Mukherjee, Sinchita; Mukherjee, Souvik; Narayanasamy, K.; Poddar, Sonia; Roy, N.; Sengupta, Priya; Sharma, Sangeeta; Sur, Dipika; Sutradhar, Debabrata; Wagener, Diane K.

doi:10.1016/j.meegid.2008.02.009

Cited by 13 publications

(9 citation statements)

References 30 publications

(30 reference statements)

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“…MBL serum concentration influences susceptibility to and clinical course of many infectious and chronic diseases (30). We have shown (20) that, although the frequencies of haplotypes in our study population associated with high (53%) and deficient (20%) levels of MBL serum concentration are comparable to those observed worldwide (49% and 22%), the frequencies of intermediate (1.5%) and low (24%) haplotypes are significantly different from the global frequencies (15% and 13%) (17). The significantly higher frequency of the low-secretor haplotype (and, consequently, a lower frequency of intermediate-secretor haplotypes) is noteworthy.…”

Section: Resultsmentioning

confidence: 88%

“…We have sampled a large number of residents of a socioeconomically depressed region of India, who live in unhygienic conditions and are therefore exposed to a high load of pathogens as evidenced by recurrent outbreaks of typhoid and cholera. In each sampled individual, we have resequenced these 12 genes and have cataloged extensive genomic variation (20). For drawing appropri- …”

Section: Discussionmentioning

confidence: 99%

“…We have recently documented extensive variation that included the discovery of 259 novel variants, in 12 innate immunity genes (cathelicidin antimicrobial peptide, CAMP; ␣-defensins, DEFA4, DEFA5 and DEFA6; ␤-defensin, DEFB1; mannose binding lectin, MBL2; and TLRs 1, 2, 4, 5, 6 and 9) in an Indian population resident in a region with high load of pathogens and have shown that the haplotype structures of these genes differ markedly in this population compared with the HapMap populations (20). Parenthetically, we note that although genes involved in innate immunity continue to be identified, the 12 genes chosen by us are some of the earliest identified innate immunity genes for which there was extensive functional data and no copy number variation in the human genome.…”

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confidence: 99%

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Signatures of natural selection are not uniform across genes of innate immune system, but purifying selection is the dominant signature

Mukherjee

Sarkar-Roy

Wagener

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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102

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We tested the opposing views concerning evolution of genes of the innate immune system that (i) being evolutionary ancient, the system may have been highly optimized by natural selection and therefore should be under purifying selection, and (ii) the system may be plastic and continuing to evolve under balancing selection. We have resequenced 12 important innate-immunity genes (CAMP, DEFA4, DEFA5, DEFA6, DEFB1, MBL2, and TLRs 1, 2, 4, 5, 6, and 9) in healthy volunteers (n ‫؍‬ 171) recruited from a region of India with high microbial load. We have compared these data with those of European-Americans (EUR) and African-Americans (AFR). We have found that most of the human haplotypes are many mutational steps away from the ancestral (chimpanzee) haplotypes, indicating that humans may have had to adapt to new pathogens. The haplotype structures in India are significantly different from those of EUR and AFR populations, indicating local adaptation to pathogens. In these genes, there is (i) generally an excess of rare variants, (ii) high, but variable, degrees of extended haplotype homozygosity, (iii) low tolerance to nonsynonymous changes, (iv) essentially one or a few high-frequency haplotypes, with star-like phylogenies of other infrequent haplotypes radiating from the modal haplotypes. Purifying selection is the most parsimonious explanation operating on these innate immunity genes. This genetic surveillance system recognizes motifs in pathogens that are perhaps conserved across a broad range of pathogens. Hence, functional constraints are imposed on mutations that diminish the ablility of these proteins to detect pathogens. extended haplotype homozygosity ͉ haplotype networks ͉ neutrality tests ͉ resequencing

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Section: Resultsmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Signatures of natural selection are not uniform across genes of innate immune system, but purifying selection is the dominant signature

Mukherjee

Sarkar-Roy

Wagener

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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102

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“…32 A positive selection for immune genes has also been extensively studied in human populations. 38 Zebrafish homologs of human disease genes in general displayed a lower ratio of nonsynonymous to synonymous SNVs. This observation was statistically significant, suggesting conserved sequence and function as the driving force in evolution of these genes.…”

Section: Discussionmentioning

confidence: 99%

A Sequence-Based Variation Map of Zebrafish

et al. 2013

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Zebrafish (Danio rerio) is a popular vertebrate model organism largely deployed using outbred laboratory animals. The nonisogenic nature of the zebrafish as a model system offers the opportunity to understand natural variations and their effect in modulating phenotype. In an effort to better characterize the range of natural variation in this model system and to complement the zebrafish reference genome project, the whole genome sequence of a wild zebrafish at 39-fold genome coverage was determined. Comparative analysis with the zebrafish reference genome revealed approximately 5.2 million single nucleotide variations and over 1.6 million insertion-deletion variations. This dataset thus represents a new catalog of genetic variations in the zebrafish genome. Further analysis revealed selective enrichment for variations in genes involved in immune function and response to the environment, suggesting genome-level adaptations to environmental niches. We also show that human disease gene orthologs in the sequenced wild zebrafish genome show a lower ratio of nonsynonymous to synonymous single nucleotide variations.

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“…Among functionally important IR genes, the Major Histocompatibility Complex (MHC) genes represent a particularly suitable tool for investigating functionally important variation and natural selection [ 37 – 40 ]. In addition, polymorphisms in other IR genes, such as cytokine-coding genes have been shown to represent informative markers for population diversity studies [ 41 – 43 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic diversity and population structure of African village dogs based on microsatellite and immunity-related molecular markers

et al. 2018

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The village and street dogs represent a unique model of canine populations. In the absence of selective breeding and veterinary care, they are subject mostly to natural selection. Their analyses contribute to understanding general mechanisms governing the genetic diversity, evolution and adaptation. In this study, we analyzed the genetic diversity and population structure of African village dogs living in villages in three different geographical areas in Northern Kenya. Data obtained for neutral microsatellite molecular markers were compared with those computed for potentially non-neutral markers of candidate immunity-related genes. The neutral genetic diversity was similar to other comparable village dog populations studied so far. The overall genetic diversity in microsatellites was higher than the diversity of European pure breeds, but it was similar to the range of diversity observed in a group composed of many European breeds, indicating that the African population has maintained a large proportion of the genetic diversity of the canine species as a whole. Microsatellite marker diversity indicated that the entire population is subdivided into three genetically distinct, although closely related subpopulations. This genetical partitioning corresponded to their geographical separation and the observed gene flow well correlated with the communication patterns among the three localities. In contrast to neutral microsatellites, the genetic diversity in immunity-related candidate SNP markers was similar across all three subpopulations and to the European group. It seems that the genetic structure of this particular population of Kenyan village dogs is mostly determined by geographical and anthropogenic factors influencing the gene flow between various subpopulations rather than by biological factors, such as genetic contribution of original migrating populations and/or the pathogen-mediated selection. On the other hand, the study of oldest surviving dogs suggested a biological mechanism, i.e. a possible advantage of the overal heterozygosity marked by the the microsatellite loci analyzed.

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Genetic variation and haplotype structures of innate immunity genes in eastern India

Cited by 13 publications

References 30 publications

Signatures of natural selection are not uniform across genes of innate immune system, but purifying selection is the dominant signature

Signatures of natural selection are not uniform across genes of innate immune system, but purifying selection is the dominant signature

A Sequence-Based Variation Map of Zebrafish

Genetic diversity and population structure of African village dogs based on microsatellite and immunity-related molecular markers

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