Prevalence of common disease-associated variants in Asian Indians

<p>Abstract</p> <p>Background</p> <p>Asian Indians display a high prevalence of diseases linked to changes in diet and environment that have arisen as their lifestyle has become more westernized. Using 1200 genome-wide polymorphisms in 432 individuals from 15 Indian language groups, we have recently shown that: (i) Indians constitute a distinct population-genetic cluster, and (ii) despite the geographic and linguistic diversity of the groups they exhibit a relatively low level of genetic heterogeneity.</p> <p>Results</p> <p>We investigated the prevalence of common polymorphisms that have been associated with diseases, such as atherosclerosis (<it>ALOX5</it>), hypertension (<it>CYP3A5</it>, <it>AGT</it>, <it>GNB3</it>), diabetes (<it>CAPN10</it>, <it>TCF7L2</it>, <it>PTPN22</it>), prostate cancer (DG8S737, rs1447295), Hirschsprung disease (<it>RET</it>), and age-related macular degeneration (<it>CFH</it>, <it>LOC387715</it>). In addition, we examined polymorphisms associated with skin pigmentation (<it>SLC24A5</it>) and with the ability to taste phenylthiocarbamide (<it>TAS2R38</it>). All polymorphisms were studied in a cohort of 576 India-born Asian Indians sampled in the United States. This sample consisted of individuals whose mother tongue is one of 14 of the 22 "official" languages recognized in India as well as individuals whose mother tongue is Parsi, a cultural group that has resided in India for over 1000 years. Analysis of the data revealed that allele frequency differences between the different Indian language groups were small, and interestingly the variant alleles of <it>ALOX5 </it>g.8322G>A and g.50778G>A, and <it>PTPN22 </it>g.36677C>T were present only in a subset of the Indian language groups. Furthermore, a latitudinal cline was identified both for the allele frequencies of the SNPs associated with hypertension (<it>CYP3A5</it>, <it>AGT</it>, <it>GNB3</it>), as well as for those associated with the ability to taste phenylthiocarbamide (<it>TAS2R38</it>).</p> <p>Conclusion</p> <p>Although caution is warranted due to the fact that this US-sampled Indian cohort may not represent a random sample from India, our results will hopefully assist in the design of future studies that investigate the genetic causes of these diseases in India. Our results also support the inclusion of the Indian population in disease-related genetic studies, as it exhibits unique genotype as well as phenotype characteristics that may yield new insights into the underlying causes of common diseases that are not available in other populations.</p

Low Levels of Genetic Divergence across Geographically and Linguistically Diverse Populations from India

Ongoing modernization in India has elevated the prevalence of many complex genetic diseases associated with a western lifestyle and diet to near-epidemic proportions. However, although India comprises more than one sixth of the world's human population, it has largely been omitted from genomic surveys that provide the backdrop for association studies of genetic disease. Here, by genotyping India-born individuals sampled in the United States, we carry out an extensive study of Indian genetic variation. We analyze 1,200 genome-wide polymorphisms in 432 individuals from 15 Indian populations. We find that populations from India, and populations from South Asia more generally, constitute one of the major human subgroups with increased similarity of genetic ancestry. However, only a relatively small amount of genetic differentiation exists among the Indian populations. Although caution is warranted due to the fact that United States–sampled Indian populations do not represent a random sample from India, these results suggest that the frequencies of many genetic variants are distinctive in India compared to other parts of the world and that the effects of population heterogeneity on the production of false positives in association studies may be smaller in Indians (and particularly in Indian-Americans) than might be expected for such a geographically and linguistically diverse subset of the human population

Hypodontia: genetics and future Hypodontia: genetics and future Hypodontia: genetics and future Hypodontia: genetics and future Hypodontia: genetics and future perspectives perspectives perspectives perspectives perspectives Parimal Das Parimal Das Parima

Abstract Abstract Abstract Abstract Abstract Tooth development is a complex process of reciprocal interactions that we have only recently begun to understand. With the large number of genes involved in the odontogenic process, the opportunity for mutations to disrupt this process is high. Tooth agenesis (hypodontia) is the most common craniofacial malformation with patients missing anywhere from one tooth to their entire dentition. Hypodontia can occur in association with other developmental anomalies (syndromic) or as an isolated condition (non-syndromic). Recent advances in genetic techniques have allowed us to begin understanding the genetic processes that underlie the odontogenic process and to identify the mechanisms responsible for tooth agenesis. Thus far two genes have been identified by mutational analysis as the major causes of non-syndromic hypodontia; PAX9 and MSX1. Haploinsufficiency of either has been observed to cause the more severe forms of hypodontia whilst point mutations cause hypodontia to varying degrees of severity. With the prevalence of hypodontia having been observed to have increased during the 20 th century, the future identification and analysis of its genetic basis is essential to allow us to better treat the condition. The clinician can facilitate this process by collaborating with the human geneticist and referring patients/families with familial hypodontia for investigative research

Hypodontia: genetics and future perspectives

Tooth development is a complex process of reciprocal interactions that we have only recently begun to understand. With the large number of genes involved in the odontogenic process, the opportunity for mutations to disrupt this process is high. Tooth agenesis (hypodontia) is the most common craniofacial malformation with patients missing anywhere from one tooth to their entire dentition. Hypodontia can occur in association with other developmental anomalies (syndromic) or as an isolated condition (non-syndromic). Recent advances in genetic techniques have allowed us to begin understanding the genetic processes that underlie the odontogenic process and to identify the mechanisms responsible for tooth agenesis. Thus far two genes have been identified by mutational analysis as the major causes of non-syndromic hypodontia; PAX9 and MSX1. Haploinsufficiency of either has been observed to cause the more severe forms of hypodontia whilst point mutations cause hypodontia to varying degrees of severity. With the prevalence of hypodontia having been observed to have increased during the 20th century, the future identification and analysis of its genetic basis is essential to allow us to better treat the condition. The clinician can facilitate this process by collaborating with the human geneticist and referring patients/families with familial hypodontia for investigative research

Reciprocal Crossovers and a Positional Preference for Strand Exchange in Recombination Events Resulting in Deletion or Duplication of Chromosome 17p11.2

Smith-Magenis syndrome (SMS) is caused by an ∼4-Mb heterozygous interstitial deletion on chromosome 17p11.2 in ∼80%–90% of affected patients. Three large (∼200 kb), complex, and highly homologous (∼98%) low-copy repeats (LCRs) are located inside or flanking the SMS common deletion. These repeats, also known as “SMS-REPs,” are termed “distal,” “middle,” and “proximal.” The directly oriented distal and proximal copies act as substrates for nonallelic homologous recombination resulting in both the deletion associated with SMS and the reciprocal duplication: dup(17)(p11.2p11.2). Using restriction enzyme cis-morphism analyses and direct sequencing, we mapped the regions of strand exchange in 16 somatic-cell hybrids that harbor only the recombinant SMS-REP. Our studies showed that the sites of crossovers were distributed throughout the region of homology between the distal and proximal SMS-REPs. However, despite ∼170 kb of high homology, 50% of the recombinant junctions occurred in a 12.0-kb region within the KER gene clusters. DNA sequencing of this hotspot (positional preference for strand exchange) in seven recombinant SMS-REPs narrowed the crossovers to an ∼8-kb interval. Four of them occurred in a 1,655-bp region rich in polymorphic nucleotides that could potentially reflect frequent gene conversion. For further evaluation of the strand exchange frequency in patients with SMS, novel junction fragments from the recombinant SMS-REPs were identified. As predicted by the reciprocal-recombination model, junction fragments were also identified from this hotspot region in patients with dup(17)(p11.2p11.2), documenting reciprocity of the positional preference for strand exchange. Several potential cis-acting recombination-promoting sequences were identified within the hotspot. It is interesting that we found 2.1-kb AT-rich inverted repeats flanking the proximal and middle KER gene clusters but not the distal one. The role of any or all of these in stimulating double-strand breaks around this positional recombination hotspot remains to be explored