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Sui W.,Central Laboratory of Guilin 181st Hospital | Ou M.,Chongqing Medical University | Liang J.,BGI Shenzhen | Ding M.,Chongqing Medical University | And 16 more authors.
Gene | Year: 2013

Osteopetrosis is a rare genetically heterogeneous disorder of bone metabolism characterized by increased skeleton density. In the past, standard methods for genetic diagnosis of osteopetrosis have primarily been performed by candidate gene screening and positional cloning. However, these methods are time and labor consumptive; and the genetic basis of approximately 30% of the cases is yet to be elucidated. Here, we employed whole exome sequencing of two affected individuals from an osteopetrosis family to identify a candidate mutation in CLCN7 (Y99C). It was identified from a total of 1757 and 1728 genetic variations found in either patient, which were then distilled using filtering strategies and confirmed using Sanger sequencing. We identified this mutation in six family members, while not in population matched controls. This mutation was previously found in osteopetrosis patients by other researchers. Our evolutionary analysis also indicated that it is under extremely high selective pressure, and is likely to be critical for the correct function of ClC-7, and thus is likely to be the responsible cause of disease. Collectively, our data further indicated that mutation (Y99C) may be a cause of osteopetrosis, and highlights the use of whole exome sequencing as a valuable approach to identifying disease mutations in a cost and time efficient manner. © 2012 Elsevier B.V.

Udpa N.,University of California at San Diego | Ronen R.,University of California at San Diego | Zhou D.,University of California at San Diego | Liang J.,BGI Americas | And 24 more authors.
Genome Biology | Year: 2014

Background: Although it has long been proposed that genetic factors contribute to adaptation to high altitude, such factors remain largely unverified. Recent advances in high-throughput sequencing have made it feasible to analyze genome-wide patterns of genetic variation in human populations. Since traditionally such studies surveyed only a small fraction of the genome, interpretation of the results was limited.Results: We report here the results of the first whole genome resequencing-based analysis identifying genes that likely modulate high altitude adaptation in native Ethiopians residing at 3,500 m above sea level on Bale Plateau or Chennek field in Ethiopia. Using cross-population tests of selection, we identify regions with a significant loss of diversity, indicative of a selective sweep. We focus on a 208 kbp gene-rich region on chromosome 19, which is significant in both of the Ethiopian subpopulations sampled. This region contains eight protein-coding genes and spans 135 SNPs. To elucidate its potential role in hypoxia tolerance, we experimentally tested whether individual genes from the region affect hypoxia tolerance in Drosophila. Three genes significantly impact survival rates in low oxygen: cic, an ortholog of human CIC, Hsl, an ortholog of human LIPE, and Paf-AHα, an ortholog of human PAFAH1B3.Conclusions: Our study reveals evolutionarily conserved genes that modulate hypoxia tolerance. In addition, we show that many of our results would likely be unattainable using data from exome sequencing or microarray studies. This highlights the importance of whole genome sequencing for investigating adaptation by natural selection. © 2014 Udpa et al.; licensee BioMed Central Ltd.

Zhou D.,University of California at San Diego | Udpa N.,University of California at San Diego | Ronen R.,University of California at San Diego | Stobdan T.,University of California at San Diego | And 23 more authors.
American Journal of Human Genetics | Year: 2013

The hypoxic conditions at high altitudes present a challenge for survival, causing pressure for adaptation. Interestingly, many high-altitude denizens (particularly in the Andes) are maladapted, with a condition known as chronic mountain sickness (CMS) or Monge disease. To decode the genetic basis of this disease, we sequenced and compared the whole genomes of 20 Andean subjects (10 with CMS and 10 without). We discovered 11 regions genome-wide with significant differences in haplotype frequencies consistent with selective sweeps. In these regions, two genes (an erythropoiesis regulator, SENP1, and an oncogene, ANP32D) had a higher transcriptional response to hypoxia in individuals with CMS relative to those without. We further found that downregulating the orthologs of these genes in flies dramatically enhanced survival rates under hypoxia, demonstrating that suppression of SENP1 and ANP32D plays an essential role in hypoxia tolerance. Our study provides an unbiased framework to identify and validate the genetic basis of adaptation to high altitudes and identifies potentially targetable mechanisms for CMS treatment. © 2013 The American Society of Human Genetics.

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