[Show abstract][Hide abstract] ABSTRACT: To identify and investigate the susceptibility genes of Kashin-Beck disease (KBD) in Chinese population.
Whole-exome capturing and sequencing technology was used for the detection of genetic variations in 19 individuals from six families with high incidence of KBD. A total of 44 polymorphisms from 41 genes were genotyped from a total of 144 cases and 144 controls by using MassARRAY under the standard protocol from Sequenom. Association was applied on the data by using PLINK1.07.
In the sequencing stage, each sample showed approximately 70-fold coverage, thus covering more than 99% of the target regions. Among the single nucleotide polymorphisms (SNPs) used in the transmission disequilibrium test, 108 had a p-value of <0.01, whereas 1056 had a p-value of <0.05. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis indicates that these SNPs focus on three major pathways: regulation of actin cytoskeleton, focal adhesion, and metabolic pathways. In the validation stage, single locus effects revealed that two of these polymorphisms (rs7745040 and rs9275295) in the human leukocyte antigen (HLA)-DRB1 gene and one polymorphism (rs9473132) in CD2-associated protein (CD2AP) gene have a significant statistical association with KBD.
HLA-DRB1 and CD2AP gene were identified to be among the susceptibility genes of KBD, thus supporting the role of the autoimmune response in KBD and the possibility of shared etiology between osteoarthritis, rheumatoid arthritis, and KBD.
PLoS ONE 01/2014; 9(4):e92298. · 3.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Azoospermia is one of the major reproductive disorders which cause male infertility in humans; however, the etiology of this disease is largely unknown. In the present study, six missense mutations of WT1 gene were detected in 529 human patients with non-obstructive azoospermia (NOA), indicating a strong association between WT1 mutation and NOA. The Wilms tumor gene, Wt1, is specifically expressed in Sertoli cells (SCs) which support spermatogenesis. To examine the functions of this gene in spermatogenesis, Wt1 was deleted in adult testis using Wt1(flox) and Cre-ER(TM) mice strains. We found that inactivation of Wt1 resulted in massive germ cell death and only SCs were present in most of the seminiferous tubules which was very similar to NOA in humans. In investigating the potential mechanism for this, histological studies revealed that the blood-testis barrier (BTB) was disrupted in Wt1 deficient testes. In vitro studies demonstrated that Wt1 was essential for cell polarity maintenance in SCs. Further studies found that the expression of cell polarity associated genes (Par6b and E-cadherin) and Wnt signaling genes (Wnt4, Wnt11) were downregulated in Wt1 deficient SCs, and that the expression of Par6b and E-cadherin was regulated by Wnt4. Our findings suggest that Wt1 is important in spermatogenesis by regulating the polarity of SCs via Wnt signaling pathway and that WT1 mutation is one of the genetic causes of NOA in humans.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: To facilitate the clinical implementation of genomic medicine by next-generation sequencing, it will be critically important to obtain accurate and consistent variant calls on personal genomes. Multiple software tools for variant calling are available, but it is unclear how comparable these tools are or what their relative merits in real-world scenarios might be. METHODS: We sequenced 15 exomes from four families using the Illumina HiSeq 2000 platform and Agilent SureSelect v.2 capture kit, with ~120X mean coverage. We analyzed the raw data using near-default parameters with 5 different alignment and variant calling pipelines (SOAP, BWA-GATK, BWA-SNVer, GNUMAP, and BWA-SAMTools). We additionally sequenced a single whole genome using the Complete Genomics (CG) sequencing and analysis pipeline, with 95% of the exome region being covered by 20 or more reads per base. Finally, we attempted to validate 919 SNVs and 841 indels, including similar fractions of GATK-only, SOAP-only, and shared calls, on the MiSeq platform by amplicon sequencing with ~5000X average coverage. RESULTS: SNV concordance between five Illumina pipelines across all 15 exomes is 57.4%, while 0.5-5.1% variants were called as unique to each pipeline. Indel concordance is only 26.8% between three indel calling pipelines, even after left-normalizing and intervalizing genomic coordinates by 20 base pairs. 11% of CG variants that fall within targeted regions in exome sequencing were not called by any of the Illumina-based exome analysis pipelines. Based on targeted amplicon sequencing on the MiSeq platform, 97.1%, 60.2% and 99.1% of the GATK-only, SOAP-only and shared SNVs can be validated, but only 54.0%, 44.6% and 78.1% of the GATK-only, SOAP-only and shared indels can be validated. Additionally, our analysis of two families, one containing four individuals and the other containing seven, demonstrates additional accuracy gained in variant discovery by having access to genetic data from a multi-generational family. CONCLUSIONS: Our results suggest that more caution should be exercised in genomic medicine settings when analyzing individual genomes, including interpreting positive and negative findings with scrutiny, especially for indels. We advocate for renewed collection and sequencing of multi-generational families, so as to increase the overall accuracy of whole genomes.
Genome Medicine 03/2013; 5(3):28. · 3.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: CDK8 is either amplified or mutated in a variety of human cancers, and CDK8 functions as an oncoprotein in melanoma and colorectal cancers. Previously, we reported that loss or reduction of CDK8 results in aberrant fat accumulation in Drosophila and mammals, suggesting that CDK8 plays an important role in inhibiting lipogenesis. Epidemiological studies have identified obesity and overweight as the major risk factors of endometrial cancer, thus we examined whether CDK8 regulates endometrial cancer cell growth by using several endometrial cancer cell lines, including KLE, which express low levels of CDK8, as well as AN3 CA and HEC-1A cells, which have high levels of endogenous CDK8. We observed that ectopic expression of CDK8 in KLE cells inhibited cell proliferation and potently blocked tumor growth in an in vivo mouse model. In addition, gain of CDK8 in KLE cells blocked cell migration and invasion in transwell, wound healing and persistence of migratory directionality assays. Conversely, we observed the opposite effects in all of the aforementioned assays when CDK8 was depleted in AN3 CA cells. Similar to AN3 CA cells, depletion of CDK8 in HEC-1A cells strongly enhanced cell migration in transwell assays, while overexpression of CDK8 in HEC-1A cells blocked cell migration. Furthermore, gene profiling of KLE cells overexpressing CDK8 revealed genes whose protein products are involved in lipid metabolism, cell cycle and cell movement pathways. Finally, depletion of CDK8 increased the expression of lipogenic genes in endometrial cancer cells. Taken together, these results show a reverse correlation between CDK8 levels and several key features of the endometrial cancer cells, including cell proliferation, migration and invasion as well as tumor formation in vivo. Therefore, in contrast to the oncogenic effects of CDK8 in melanoma and colorectal cancers, our results suggest that CDK8 plays a tumor-suppressive role in endometrial cancers.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Marie Unna hereditary hypotrichosis (MUHH) is an autosomal dominant disorder characterised by coarse, wiry, twisted hair developed in early childhood and subsequent progressive hair loss. MUHH is a genetically heterogeneous disorder. No gene in 1p21.1-1q21.3 region responsible for MUHH has been identified. METHODS: Exome sequencing was performed on two affected subjects, who had normal vertex hair and modest alopecia, and one unaffected individual from a four-generation MUHH family of which our previous linkage study mapped the MUHH locus on chromosome 1p21.1-1q21.3. RESULTS: We identified a missense mutation in EPS8L3 (NM_024526.3: exon2: c.22G->A:p.Ala8Thr) within 1p21.1-1q21.3. Sanger sequencing confirmed the cosegregation of this mutation with the disease phenotype in the family by demonstrating the presence of the heterozygous mutation in all the eight affected and absence in all the seven unaffected individuals. This mutation was found to be absent in 676 unrelated healthy controls and 781 patients of other disease from another unpublished project of our group. CONCLUSIONS: Taken together, our results suggest that EPS8L3 is a causative gene for MUHH, which was helpful for advancing us on understanding of the pathogenesis of MUHH. Our study also has further demonstrated the effectiveness of combining exome sequencing with linkage information for identifying Mendelian disease genes.
Journal of Medical Genetics 10/2012; · 5.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Idiopathic azoospermia (IA) is a severe form of male infertility due to unknown causes. The HSF2 gene, encoding the heat shock transcription factor 2, had been suggested to play a significant role in the spermatogenesis process since the Hsf2-knockout male mice showed spermatogenesis defects. To examine whether HSF2 is involved in the pathogenesis of IA in human, we sequenced all the exons of HSF2 in 766 patients diagnosed with IA and 521 proven fertile men. A number of coding mutations private to the patient group, which include three synonymous mutations and five missense mutations, were identified. Of the missense mutations, our functional assay demonstrated that one heterozygous mutation, R502H, caused a complete loss of HSF2 function and that the mutant suppressed the normal function of the wild-type (WT) allele through a dominant-negative effect, thus leading to the dominant penetrance of the mutant allele. These results support a role for HSF2 in the pathogenesis of IA and further implicate this transcription factor as a potential therapeutic target.
[Show abstract][Hide abstract] ABSTRACT: Disseminated superficial actinic porokeratosis (DSAP) is an autosomal dominantly inherited epidermal keratinization disorder whose etiology remains unclear. We performed exome sequencing in one unaffected and two affected individuals from a DSAP family. The mevalonate kinase gene (MVK) emerged as the only candidate gene located in previously defined linkage regions after filtering against existing SNP databases, eight HapMap exomes and 1000 Genomes Project data and taking into consideration the functional implications of the mutations. Sanger sequencing in 57 individuals with familial DSAP and 25 individuals with sporadic DSAP identified MVK mutations in 33% and 16% of these individuals (cases), respectively. All 14 MVK mutations identified in our study were absent in 676 individuals without DSAP. Our functional studies in cultured primary keratinocytes suggest that MVK has a role in regulating calcium-induced keratinocyte differentiation and could protect keratinocytes from apoptosis induced by type A ultraviolet radiation. Our results should help advance the understanding of DSAP pathogenesis.
[Show abstract][Hide abstract] ABSTRACT: STUDY DESIGN:: This is a prospective study of artificial disc replacement combined with cage fusion for the treatment of multi-level cervical disc herniation. OBJECTIVE:: To evaluate the clinical outcome of Bryan cervical disc replacement combined with adjacent segment cage fusion in the treatment of patients with multi-level cervical disc herniation. To observe neurological improvement and interpret the radiographic findings. SUMMARY OF BACKGROUND DATA:: It is generally considered that one-level cervical disc replacement had an excellent intermediate clinical outcome. There was no final conclusion about the disc replacement for the treatment of multi-level cervical disc disease. The negative factors include possibile complication, high cost, and contraindication for disc replacement at one of the multi-segments. Disc replacement combined with adjacent segment cage fusion may be an option for the treatment of multi-level cervical disc disease for certain patients. METHODS:: There were 26 patients with multi-level cervical disc herniation who underwent single-level disc replacement and adjacent segment cage fusion. Of the patients, there were 17 male and 9 female, aged between 35 and 63 (mean age 47▒y). The herniated disc was located at C3-4, C4-5 in 1 case, C4-5, C5-6 in 11cases, C5-6, C6-7 in 7 cases, C4-5, C6-7 in 3 cases, and C4-5, C5-6, C6-7 in 4 cases. There were 12 cases with myelopathy and 14 patients with radiculopathy. The stabilization and the range of motion of implanted disc, the fusion of cage and the displacement of cage were observed on dynamic radiograph postoperatively. The clinical symptom and the neurological function were evaluated based on the JOA score (17 points), NDI (neck disability index) score and odom's criteria RESULTS:: All patients underwent single-level Bryan disc replacement and cage fusion on adjacent segment. The replacement segment and fusion segment were located next to each other among 23 patients. They were not next to each other in 3 cases. The follow-up was 24 months to 47 months. Definite stabilization was achieved for all Bryan discs. The average range of motion at replaced level was 9.5 degrees postoperatively. Solid fusion was achieved in all cage. There was no subsidence or displacement of cage. The JOA score (17 points) rose from 9.2 to 13.5 at final follow up. The NDI (neck disability index) was reduced from 40.8 to 28.5 at final follow-up. The clinical success (excellent/good/fair) based on Odom's Criteria were 84.6%. CONCLUSION:: Definite stabilization and satisfactory mobility were achieved after cervical disc replacement and cage fusion. This provides an effective option for the treatment of multi - level cervical disc herniation. The evaluation of high fusion rate of cage may need to accumulate more clinical cases.
[Show abstract][Hide abstract] ABSTRACT: We sequenced whole exomes of ten clear cell renal cell carcinomas (ccRCCs) and performed a screen of ∼1,100 genes in 88 additional ccRCCs, from which we discovered 12 previously unidentified genes mutated at elevated frequencies in ccRCC. Notably, we detected frequent mutations in the ubiquitin-mediated proteolysis pathway (UMPP), and alterations in the UMPP were significantly associated with overexpression of HIF1α and HIF2α in the tumors (P = 0.01 and 0.04, respectively). Our findings highlight the potential contribution of UMPP to ccRCC tumorigenesis through the activation of the hypoxia regulatory network.
[Show abstract][Hide abstract] ABSTRACT: A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries of genetic variation, like allele frequencies, are also correlated with recombination rate and whether these correlations can be explained solely by negative selection against deleterious mutations or whether positive selection acting on favorable alleles is also required. Here we attempt to address these questions by analyzing three different genome-wide resequencing datasets from European individuals. We document several significant correlations between different genomic features. In particular, we find that average minor allele frequency and diversity are reduced in regions of low recombination and that human diversity, human-chimp divergence, and average minor allele frequency are reduced near genes. Population genetic simulations show that either positive natural selection acting on favorable mutations or negative natural selection acting against deleterious mutations can explain these correlations. However, models with strong positive selection on nonsynonymous mutations and little negative selection predict a stronger negative correlation between neutral diversity and nonsynonymous divergence than observed in the actual data, supporting the importance of negative, rather than positive, selection throughout the genome. Further, we show that the widespread presence of weakly deleterious alleles, rather than a small number of strongly positively selected mutations, is responsible for the correlation between neutral genetic diversity and recombination rate. This work suggests that natural selection has affected multiple aspects of linked neutral variation throughout the human genome and that positive selection is not required to explain these observations.
[Show abstract][Hide abstract] ABSTRACT: Here we present an adaptation of NimbleGen 2.1M-probe array sequence capture for whole exome sequencing using the Illumina Genome Analyzer (GA) platform. The protocol involves two-stage library construction. The specificity of exome enrichment was approximately 80% with 95.6% even coverage of the 34 Mb target region at an average sequencing depth of 33-fold. Comparison of our results with whole genome shot-gun resequencing results showed that the exome SNP calls gave only 0.97% false positive and 6.27% false negative variants. Our protocol is also well suited for use with whole genome amplified DNA. The results presented here indicate that there is a promising future for large-scale population genomics and medical studies using a whole exome sequencing approach.
Science China. Life sciences 10/2011; 54(10):945-52. · 2.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exome sequencing, which allows the global analysis of protein coding sequences in the human genome, has become an effective and affordable approach to detecting causative genetic mutations in diseases. Currently, there are several commercial human exome capture platforms; however, the relative performances of these have not been characterized sufficiently to know which is best for a particular study.
We comprehensively compared three platforms: NimbleGen's Sequence Capture Array and SeqCap EZ, and Agilent's SureSelect. We assessed their performance in a variety of ways, including number of genes covered and capture efficacy. Differences that may impact on the choice of platform were that Agilent SureSelect covered approximately 1,100 more genes, while NimbleGen provided better flanking sequence capture. Although all three platforms achieved similar capture specificity of targeted regions, the NimbleGen platforms showed better uniformity of coverage and greater genotype sensitivity at 30- to 100-fold sequencing depth. All three platforms showed similar power in exome SNP calling, including medically relevant SNPs. Compared with genotyping and whole-genome sequencing data, the three platforms achieved a similar accuracy of genotype assignment and SNP detection. Importantly, all three platforms showed similar levels of reproducibility, GC bias and reference allele bias.
We demonstrate key differences between the three platforms, particularly advantages of solutions over array capture and the importance of a large gene target set.
[Show abstract][Hide abstract] ABSTRACT: Exome sequencing has identified the causes of several Mendelian diseases, although it has rarely been used in a clinical setting to diagnose the genetic cause of an idiopathic disorder in a single patient. We performed exome sequencing on a pedigree with several members affected with attention deficit/hyperactivity disorder (ADHD), in an effort to identify candidate variants predisposing to this complex disease. While we did identify some rare variants that might predispose to ADHD, we have not yet proven the causality for any of them. However, over the course of the study, one subject was discovered to have idiopathic hemolytic anemia (IHA), which was suspected to be genetic in origin. Analysis of this subject's exome readily identified two rare non-synonymous mutations in PKLR gene as the most likely cause of the IHA, although these two mutations had not been documented before in a single individual. We further confirmed the deficiency by functional biochemical testing, consistent with a diagnosis of red blood cell pyruvate kinase deficiency. Our study implies that exome and genome sequencing will certainly reveal additional rare variation causative for even well-studied classical Mendelian diseases, while also revealing variants that might play a role in complex diseases. Furthermore, our study has clinical and ethical implications for exome and genome sequencing in a research setting; how to handle unrelated findings of clinical significance, in the context of originally planned complex disease research, remains a largely uncharted area for clinicians and researchers.
Discovery medicine 07/2011; 12(62):41-55. · 2.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pathologic changes of demyelination after spinal cord injury (SCI) significantly impair functional recovery of lesioned spinal cord. At present, transplantation of myelinating cells is regarded as a promising strategy for treating demyelination following SCI. Hence, the In vitro culture and growth, differentiation and proliferation of oligodendrocyte precursor cells (OPCs) were intensively investigated in this study.
In vitro cells from cerebral cortices of neonatal rats were primarily cultured and OPCs were then separated by shaking process and differential adhesion. Following cultured in the conditional medium, growth pattern and differentiation of OPCs were continuously studied by both light microscopy and scanning electron microscopy. Furthermore, maturation of OPCs was detected immunochemically and proliferative ability of OPCs In vitro was also evaluated by methyl thiazolyl tetrazolium (MTT) assay.
The distinct stratification of glial cells usually developed around 9-10 days in the primary culture. The OPCs were found primarily living on the surface of confluent astrocytes and these cells typically displayed the simple appearance of immature cells. Furthermore, the OPCs progressively developed in the conditional medium, and these differentiated cells underwent dramatic changes of morphology and also expressed different specific markers. Moreover, the OPCs also proved by MTT assay to proliferate significantly while cultured In vitro.
Demyelination prevents recovery of neural function following SCI. Demyelination has already become a potential therapeutic target for this insidious and challenging problem. The In vitro culture and biological characteristics of OPCs are fundamental and necessary for further investigation of cell transplantation in vivo. Growth pattern, differentiation and proliferation are very vital for therapeutical effects of OPCs following transplantation after SCI.
Neurological Research 07/2011; 33(6):593-9. · 1.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have identified two families with a previously undescribed lethal X-linked disorder of infancy; the disorder comprises a distinct combination of an aged appearance, craniofacial anomalies, hypotonia, global developmental delays, cryptorchidism, and cardiac arrhythmias. Using X chromosome exon sequencing and a recently developed probabilistic algorithm aimed at discovering disease-causing variants, we identified in one family a c.109T>C (p.Ser37Pro) variant in NAA10, a gene encoding the catalytic subunit of the major human N-terminal acetyltransferase (NAT). A parallel effort on a second unrelated family converged on the same variant. The absence of this variant in controls, the amino acid conservation of this region of the protein, the predicted disruptive change, and the co-occurrence in two unrelated families with the same rare disorder suggest that this is the pathogenic mutation. We confirmed this by demonstrating a significantly impaired biochemical activity of the mutant hNaa10p, and from this we conclude that a reduction in acetylation by hNaa10p causes this disease. Here we provide evidence of a human genetic disorder resulting from direct impairment of N-terminal acetylation, one of the most common protein modifications in humans.
The American Journal of Human Genetics 06/2011; 89(1):28-43. · 11.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Estimation of allele frequency is of fundamental importance in population genetic analyses and in association mapping. In most studies using next-generation sequencing, a cost effective approach is to use medium or low-coverage data (e.g., < 15X). However, SNP calling and allele frequency estimation in such studies is associated with substantial statistical uncertainty because of varying coverage and high error rates.
We evaluate a new maximum likelihood method for estimating allele frequencies in low and medium coverage next-generation sequencing data. The method is based on integrating over uncertainty in the data for each individual rather than first calling genotypes. This method can be applied to directly test for associations in case/control studies. We use simulations to compare the likelihood method to methods based on genotype calling, and show that the likelihood method outperforms the genotype calling methods in terms of: (1) accuracy of allele frequency estimation, (2) accuracy of the estimation of the distribution of allele frequencies across neutrally evolving sites, and (3) statistical power in association mapping studies. Using real re-sequencing data from 200 individuals obtained from an exon-capture experiment, we show that the patterns observed in the simulations are also found in real data.
Overall, our results suggest that association mapping and estimation of allele frequencies should not be based on genotype calling in low to medium coverage data. Furthermore, if genotype calling methods are used, it is usually better not to filter genotypes based on the call confidence score.
[Show abstract][Hide abstract] ABSTRACT: This is a prospective, consecutive series study to determine the role of the Bryan artificial cervical disc replacement to treat the isolated cervical disc herniation for Chinese patients.
To evaluate the intermediate clinical outcome and its limitations of Bryan cervical disc replacement in the management of isolated cervical disc herniation in Chinese patients. Observing neurological improvement and the radiographic finding.
Most people believe that anterior cervical fusion is a factor that shall not be ignored in adjacent segment degeneration. Artificial cervical disc replacement, as a nonfusion technique, may offer a solution to this problem. The clinical outcome of cervical arthroplasty in oriental patients is not often seen in English literature. The variation of anatomic index in Asian patients was also not considered enough.
There were consecutive series of 45 patients with cervical disc herniation. The herniated disc was located at C3-4 in 2 cases, at C4-5 in 8 cases, at C5-6 in 24 cases, at C6-7 in 5 cases, at C4-5, 5-6 in 2 cases, at C3,4, 5-6 in 1 cases, and at C 5-6, 6.7 in 3 cases. There were 19 patients with myelopathy and 26 patients with radiculopathy. A total of 51 sets of Bryan cervical disc prosthesis were implanted. The follow-up ranges from 24 to 70 months. The clinical symptom and the neurological function were evaluated. The level of stableness and mobility at the implanting location were observed on dynamic radiograph postoperatively.
A total of 51 Bryan cervical disc prosthesis were implanted. Single-level disc was replaced in 39 cases whereas bilevel in 6 cases. The follow-up ranges from 24 to 70 months, with an average of 35 months. Patients showed significant improvement in neurological symptoms. The JOA score (17 points) was from 10.2 increased to 15.4 at final follow-up. The neck disability index was from 43.5 reduced to 28.4 at final follow-up. The clinical success (excellent/good/fair) according to Odom' Criteria were 89.8%. The average range of motion at implant level was 9.3 degrees, postoperatively. Migration of artificial disc greater than 2 mm was not observed. Resorption at the inferior edge of anterior surface of upper vertebral body were seen in 3 patients, Two patients had II grade heterotopic ossification. One patient had a definite spontaneous fusion of treated segment after 4 years of follow-up. There was some difficulty for exact matched implant in small group patients owing to the variation of anatomic index in oriental patients.
Cervical arthroplasty had a good intermediate clinical outcome for oriental patients. Definite stabilization and satisfactory mobility were achieved after surgery, with significant neurological symptom improvement observed. For better matched implant, more shapes/sizes of artificial cervical disc need to be made available for the oriental patients.
[Show abstract][Hide abstract] ABSTRACT: Residents of the Tibetan Plateau show heritable adaptations to extreme altitude. We sequenced 50 exomes of ethnic Tibetans, encompassing coding sequences of 92% of human genes, with an average coverage of 18x per individual. Genes showing population-specific allele frequency changes, which represent strong candidates for altitude adaptation, were identified. The strongest signal of natural selection came from endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1), a transcription factor involved in response to hypoxia. One single-nucleotide polymorphism (SNP) at EPAS1 shows a 78% frequency difference between Tibetan and Han samples, representing the fastest allele frequency change observed at any human gene to date. This SNP's association with erythrocyte abundance supports the role of EPAS1 in adaptation to hypoxia. Thus, a population genomic survey has revealed a functionally important locus in genetic adaptation to high altitude.
[Show abstract][Hide abstract] ABSTRACT: A single-base pair resolution silkworm genetic variation map was constructed from 40 domesticated and wild silkworms, each sequenced to approximately threefold coverage, representing 99.88% of the genome. We identified ~16 million single-nucleotide polymorphisms, many indels, and structural variations. We find that the domesticated silkworms are clearly genetically differentiated from the wild ones, but they have maintained large levels of genetic variability, suggesting a short domestication event involving a large number of individuals. We also identified signals of selection at 354 candidate genes that may have been important during domestication, some of which have enriched expression in the silk gland, midgut, and testis. These data add to our understanding of the domestication processes and may have applications in devising pest control strategies and advancing the use of silkworms as efficient bioreactors.