Bi-allelic Single Nucleotide Variants Research Articles

Characterization of the Common Genetic Variation in the Spanish Population of Navarre.

Large-scale genomic studies have significantly increased our knowledge of genetic variability across populations. Regional genetic profiling is essential for distinguishing common benign variants from disease-causing ones. To this end, we conducted a comprehensive characterization of exonic variants in the population of Navarre (Spain), utilizing whole genome sequencing data from 358 unrelated individuals of Spanish origin. Our analysis revealed 61,410 biallelic single nucleotide variants (SNV) within the Navarrese cohort, with 35% classified as common (MAF > 1%). By comparing allele frequency data from 1000 Genome Project (excluding the Iberian cohort of Spain, IBS), Genome Aggregation Database, and a Spanish cohort (including IBS individuals and data from Medical Genome Project), we identified 1069 SNVs common in Navarre but rare (MAF ≤ 1%) in all other populations. We further corroborated this observation with a second regional cohort of 239 unrelated exomes, which confirmed 676 of the 1069 SNVs as common in Navarre. In conclusion, this study highlights the importance of population-specific characterization of genetic variation to improve allele frequency filtering in sequencing data analysis to identify disease-causing variants.

Expanding the allelic spectrum of ELOVL4-related autosomal recessive neuro-ichthyosis.

Very long-chain fatty acids (VLCFAs) composed of more than 20 carbon atoms are essential in the biosynthesis of cell membranes in the brain, skin, and retina. VLCFAs are elongated beyond 28 carbon atoms by ELOVL4 enzyme. Variants in ELOVL4 are associated with three Mendelian disorders: autosomal dominant (AD) Stargardt-like macular dystrophy type 3, AD spinocerebellar ataxia, and autosomal recessive disorder congenital ichthyosis, spastic quadriplegia and impaired intellectual development (ISQMR). Only seven subjects from five unrelated families with ISQMR have been described, all of which have biallelic single-nucleotide variants. We performed clinical exome sequencing on probands from four unrelated families with neuro-ichthyosis. We identified three novel homozygous ELOVL4 variants. Two of the families originated from the same Saudi tribe and had the exact homozygous exonic deletion in ELOVL4, while the third and fourth probands had two different novel homozygous missense variants. Seven out of the eight affected subjects had profound developmental delay, epilepsy, axial hypotonia, peripheral hypertonia, and ichthyosis. Delayed myelination and corpus callosum hypoplasia were seen in two of five subjects with brain magnetic rosonance imaging and cerebral atrophy in three. Our study expands the allelic spectrum of ELOVL4-related ISQMR. The detection of the same exonic deletion in two unrelated Saudi family from same tribe suggests a tribal founder mutation.

Association Analysis on Alzheimer’s Disease Sequencing Project (ADSP) 16,905 Whole‐Genome Sequence Data

AbstractBackgroundThe Alzheimer’s Disease Sequencing Project (ADSP) has released the R3 dataset of whole‐genome sequencing (WGS) from 16,905 samples collected by 17 study cohorts across three major populations including 10,651 Non‐Hispanic Whites, 3,212 Hispanics, 2,874 African Americans, and 168 others. The release also includes a callset of 206 million biallelic single nucleotide variants (SNVs), 16 million biallelic insertion/deletions (INDELs), and 28 million multiallelic variants. Leveraging this dataset, we are conducting association analysis for variants, genes, and gene sets to identify genetic risk for Alzheimer’s Disease (AD).MethodWe assembled the sample list, kept only genetically unique individuals, and removed samples with unclear AD diagnoses. Samples were further removed if they had >10 Standard Deviation (SD) on any ADSP provided quality metrics including genotype missing rate, singleton rate, heterozygous/homozygous ratio, and transition/transversion ratio. Multiallelic variants were split into biallelic variants and, after QC, merged with the biallelic callset. We filtered variants if they did not obtain the GATK “pass”, were monomporphic, has an allele balance for heterozygous (ABHet) were <0.25 or >0.75, or had a genotype missing rate >0.05. RUTH was used to perform a robust unified Hardy‐Weinberg equilibrium test. We applied GENESIS PC‐AiR to conduct principal component (PC) analysis. We are performing association analyses with two approaches: using all samples while adjusting for genetic ancestry, and within population‐specific groups defined by PC clustering (10 SD) around reference populations from the Human Genome Diversity Project. Our analytical model will adjust for sex, PCs, APOE, and technical covariates.ResultThe merged biallelic and multiallelic callset contained 223 million variants. The minor allele frequency distribution (MAF) is 88.2% MAF<0.001, 6.5% 0.001<=MAF<0.01, 2.3% 0.01<=MAF<0.05, and 3.0% MAF>=0.05. PCs within the ADSP data have been generated. We are initiating association analyses including single variant analysis (using GENESIS), gene based analyses (using SKAT‐O) and rare noncoding variant set based testing (using STAAR).ConclusionWith this project, we will examine known and identify novel AD‐related variants. The dataset consists of participants from diverse genetic ancestry that will enable us to investigate how AD‐associated genetic risk factors differ by populations.

Runs of homozygosity in Swiss goats reveal genetic changes associated with domestication and modern selection

BackgroundThe domestication of goat (Capra hircus) started 11,000 years ago in the fertile crescent. Breed formation in the nineteenth century, establishment of herd books, and selection for specific traits resulted in 10 modern goat breeds in Switzerland. We analyzed whole-genome sequencing (WGS) data from 217 modern goats and nine wild Bezoar goats (Capra aegagrus). After quality control, 27,728,288 biallelic single nucleotide variants (SNVs) were used for the identification of runs of homozygosity (ROH) and the detection of ROH islands.ResultsAcross the 226 caprine genomes from 11 populations, we detected 344 ROH islands that harbor 1220 annotated genes. We compared the ROH islands between the modern breeds and the Bezoar goats. As a proof of principle, we confirmed a signature of selection, which contains the ASIP gene that controls several breed-specific coat color patterns. In two other ROH islands, we identified two missense variants, STC1:p.Lys139Arg and TSHR:p.Ala239Thr, which might represent causative functional variants for domestication signatures.ConclusionsWe have shown that the information from ROH islands using WGS data is suitable for the analysis of signatures of selection and allowed the detection of protein coding variants that may have conferred beneficial phenotypes during goat domestication. We hypothesize that the TSHR:p.Ala239Thr variant may have played a role in changing the seasonality of reproduction in modern domesticated goats. The exact functional significance of the STC1:p.Lys139Arg variant remains unclear and requires further investigation. Nonetheless, STC1 might represent a new domestication gene affecting relevant traits such as body size and/or milk yield in goats.

Post-lingual non-syndromic hearing loss phenotype: a polygenic case with 2 biallelic mutations in MYO15A and MITF

BackgroundHearing loss (HL) represents the most common congenital sensory impairment with an incidence of 1–5 per 1000 live births. Non-syndromic hearing loss (NSHL) is an isolated finding that is not part of any other disorder accounting for 70% of all genetic hearing loss cases.MethodsIn the current study, we reported a polygenic mode of inheritance in an NSHL consanguineous family using exome sequencing technology and we evaluated the possible effect of the detected single nucleotide variants (SNVs) using in silico methods.ResultsTwo bi-allelic SNVs were detected in the affected patients; a MYO15A (. p.V485A) variant, and a novel MITF (p.P338L) variant. Along with these homozygous mutations, we detected two heterozygous variants in well described hearing loss genes (MYO7A and MYH14). The novel MITF p. Pro338Leu missense mutation was predicted to change the protein structure and function.ConclusionA novel MITF mutation along with a previously described MYO15A mutation segregate with an autosomal recessive non-syndromic HL case with a post-lingual onset. The findings highlight the importance of carrying whole exome sequencing for a comprehensive assessment of HL genetic heterogeneity.

Whole Genome Sequencing and Re-sequencing of the Sable Antelope (Hippotragus niger): A Resource for Monitoring Diversity in ex Situ and in Situ Populations.

Genome-wide assessment of genetic diversity has the potential to increase the ability to understand admixture, inbreeding, kinship and erosion of genetic diversity affecting both captive (ex situ) and wild (in situ) populations of threatened species. The sable antelope (Hippotragus niger), native to the savannah woodlands of sub-Saharan Africa, is a species that is being managed ex situ in both public (zoo) and private (ranch) collections in the United States. Our objective was to develop whole genome sequence resources that will serve as a foundation for characterizing the genetic status of ex situ populations of sable antelope relative to populations in the wild. Here we report the draft genome assembly of a male sable antelope, a member of the subfamily Hippotraginae (Bovidae, Cetartiodactyla, Mammalia). The 2.596 Gb draft genome consists of 136,528 contigs with an N50 of 45.5 Kbp and 16,927 scaffolds with an N50 of 4.59 Mbp. De novo annotation identified 18,828 protein-coding genes and repetitive sequences encompassing 46.97% of the genome. The discovery of single nucleotide variants (SNVs) was assisted by the re-sequencing of seven additional captive and wild individuals, representing two different subspecies, leading to the identification of 1,987,710 bi-allelic SNVs. Assembly of the mitochondrial genomes revealed that each individual was defined by a unique haplotype and these data were used to infer the mitochondrial gene tree relative to other hippotragine species. The sable antelope genome constitutes a valuable resource for assessing genome-wide diversity and evolutionary potential, thereby facilitating long-term conservation of this charismatic species.