Pitfalls in homozygosity mapping.
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ABSTRACT:
SUBMITTER: Miano MG
PROVIDER: S-EPMC1288578 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Premature ovarian insufficiency (POI) is defined as a primary ovarian defect characterized by absent menarche (primary amenorrhea) or premature depletion of ovarian follicles before the age of 40 (secondary amenorrhea) with hypergonadotropism and hypoestrogenism. Premature ovarian insufficiency has few known genetic causes but in familial cases a genetic link is often suspected. A large consanguineous family with three female affected with POI was investigated. All samples including 3 affected and 5 unaffecd underwent whole genome SNP genotyping using Affymetric Axiom_GW_Hu_SNP array. Linkage analysis was carried out using HomozygosityMapper and Allegro softwares.Linkage analysis mapped the disease phenotype to long arm of chromosome 20. Sequence data analysis of potential candidate genes failed to detect any pathogenic variant.
2014-03-20 | GSE56043 | GEO
Project description:Autosomal recessive mental retardation (AR-MR) may account for up to 25% of genetic mental retardation (MR). So far, mapping of AR-MR genes in consanguineous families has resulted in six nonsyndromic genes, whereas more than 2000 genes might contribute to AR-MR. We propose to use outbred families with multiple affected siblings for AR-MR gene identification. Homozygosity mapping in ten outbred families with affected brother-sister pairs using a 250 K single nucleotide polymorphism array revealed on average 57 homozygous regions over 1 Mb in size per affected individual (range 20-74). Of these, 21 homozygous regions were shared between siblings on average (range 8-36). None of the shared regions of homozygosity (SROHs) overlapped with the nonsyndromic genes. A total of 13 SROHs had an overlap with previously reported loci for AR-MR, namely with MRT8, MRT9, MRT10 and MRT11. Among these was the longest observed SROH of 11.0 Mb in family ARMR1 on chromosome 19q13, which had 2.9 Mb (98 genes) in common with the 5.4 Mb MRT11 locus (195 genes). These data support that homozygosity mapping in outbred families may contribute to identification of novel AR-MR genes.
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Project description:Achromatopsia, or total color blindness (also referred to as "rod monochromacy"), is a severe retinal disorder characterized clinically by an inability to distinguish colors, impaired visual acuity in daylight, photophobia, and nystagmus. Inherited as an autosomal recessive trait, achromatopsia is rare in the general population (1:20,000-1:50,000). Among the Pingelapese people of the Eastern Caroline Islands, however, the disorder occurs at an extremely high frequency, as recounted in Oliver Sacks's popular book The Island of the Colorblind: 4%-10% of this island population have the disorder and approximately 30% carry the gene. This extraordinary enrichment of the disease allele most likely resulted from a sharp reduction in population in the late 18th century, in the aftermath of a typhoon and subsequent geographic and cultural isolation. To obtain insights into the genetic basis of achromatopsia, as well as into the genetic history of this region of Micronesia, a genomewide search for linkage was performed in three Pingelapese kindreds with achromatopsia. A two-step search was used with a DNA pooling strategy, followed by genotyping of individual family members. Genetic markers that displayed a shift toward homozygosity in the affected DNA pool were used to genotype individual members of the kindreds, and an achromatopsia locus was identified on 8q21-q22. A maximal multipoint LOD score of 9.5 was observed with marker D8S1707. Homozygosity was seen for three adjacent markers (D8S275, D8S1119, and D8S1707), whereas recombination was observed with the flanking markers D8S1757 and D8S270, defining the outer boundaries of the disease-gene locus that spans a distance of <6.5cM.
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Project description:Homozygosity mapping using genome-wide SNP arrys is a useful tool to map causative genes of mendelian disorders in consanguineous patients To search for LOH (loss of heterozygosity) regions we hybridized genomic DNA from a OI patient and a normal sibling against Human610quad beadarrays from Illumina (www.illumina.com). Genotyping data was analyzed with BeadStudio software (www.illumina.com)
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Project description:A consanguineous family segregating anhidrosis (recessive, familial) Shared homozygous regions were identified by comparing SNP genotyping results from four affected family members
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Project description:Premature ovarian insufficiency (POI) is defined as a primary ovarian defect characterized by absent menarche (primary amenorrhea) or premature depletion of ovarian follicles before the age of 40 (secondary amenorrhea) with hypergonadotropism and hypoestrogenism. Premature ovarian insufficiency has few known genetic causes but in familial cases a genetic link is often suspected. A large consanguineous family with three female affected with POI was investigated. All samples including 3 affected and 5 unaffecd underwent whole genome SNP genotyping using Affymetric Axiom_GW_Hu_SNP array. Linkage analysis was carried out using HomozygosityMapper and Allegro softwares.Linkage analysis mapped the disease phenotype to long arm of chromosome 20. Sequence data analysis of potential candidate genes failed to detect any pathogenic variant. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from peripheral blood samples. DNA of eight individuals including three affected subjects was used for homozygosity mapping. Genotyping was performed using the Affymetrix Axiom_GW_Hu_SNP array. Briefly, 250 ng genomic DNA was digested with Digestion Master Mix containing 2 µl NE buffer 2 (10X), 0.5 µl BSA (100X; 10 mg/ml) and 1 µl Nsp1. Digested DNA sample was ligated to Nsp1 adaptor using T4 DNA ligase and amplified by 2 µl of TITANIUM Taq DNA polymerase (50X) and 100 µM PCR primer. PCR products were purified on a Clean-Up plate (Clontech Lab, Madison, USA) and eluted by RB buffer. Purified PCR products were fragmented using Fragmentation Reagent (0.05U/µl DNase 1) for 35 minutes at 37°C followed by labeling of fragmented samples with Labeling Master Mix (30 mM GeneChip DNA Labeling Reagent, 30 U/µl Terminal Deoxynucleotidyl Transferase) for 4 hours at 37°C. Labeled samples were hybridized to Axiom_GW_Hu_SNP array by mixing the sample with Hybridization Master Mix, denatured on thermoblock and loaded on to Array. Array was then placed in a hybridization oven (GeneChip Hybridization Oven 640, USA) for 16-18 hours. After hybridization, array was washed and stained on an automated Fluidic Station 450 followed by scanning on GeneChip Scanner 3000 7G using GeneChip Operating Software (GCOS).
2014-03-20 | E-GEOD-56043 | biostudies-arrayexpress
Project description:BackgroundSnakebites are a public health problem in Nicaragua: it is a tropical developing country, venomous snakes are present and there are reports of snakebites treated both in the formal and informal health care system. We aimed to produce an incidence map using data reported by the health care system that would be used to allocate resources. However, this map may suffer from case detection bias and decisions based on this map will neglect snakebite victims who do not receive healthcare. To avoid this error, we try to identify where underreporting is likely based on available information.Method and findingsThe Nicaraguan municipalities are categorized by precipitation, altitude and geographical location into regions of assumed homogenous snake prevalence. Socio-economic and healthcare variables hypothesized to be related to underreporting of snakebites are aggregated into an index. The environmental region variable, the underreporting index and three demographic variables (rurality, sex and age distribution) are entered in a Poisson regression model of municipality-level snakebite incidence. In this model, the underreporting index is non-linearly associated with snakebite incidence, a finding we attribute to underreporting in the most deprived municipalities. The municipalities with the worst scoring on the underreporting index and those with combined low reported incidence and large rural population are identified as likely underreporting. 3,286 snakebite cases were reported in 2005-2009, corresponding to a 5-year incidence of 56 bites per 100,000 inhabitants (municipality range: 0-600 cases per 100,000 inhabitants).ConclusionsUsing publicly available data, we identified areas likely to be underreporting snakebites and highlighted these areas instead of leaving them "white" on the incidence map. The effects of the case detection bias on the distribution of resources against snakebites could decrease. Although not yet verified empirically, our study provides an example of how snake bite epidemiology may be investigated in similar settings worldwide at a low cost.
| S-EPMC2990701 | biostudies-literature
Project description:Homozygosity mapping using genome-wide SNP arrys is a useful tool to map causative genes of mendelian disorders in consanguineous patients To search for LOH (loss of heterozygosity) regions we hybridized genomic DNA from a OI patient and a normal sibling against Human610quad beadarrays from Illumina (www.illumina.com). Genotyping data was analyzed with BeadStudio software (www.illumina.com) Genomic DNAs from OI affected individual and non-affected sibling were hybridized each on an Illumina Human610Quad Genotyping BeadChip. Image data was analyzed using Beadstudio 3.1.3 software. CNV and LOH (larger than 1 Mb) analysis was performed using the cnvPartition 2.3.4. It was considered as a region of interest those showing LOH in the affected individual but not in the non-affected sibling.
2010-11-01 | E-GEOD-21958 | biostudies-arrayexpress
Project description:A consanguineous family segregating anhidrosis (recessive, familial) Shared homozygous regions were identified by comparing SNP genotyping results from four affected family members Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from peripheral blood samples.
2014-09-05 | E-GEOD-61122 | biostudies-arrayexpress
Project description:PURPOSE: Autosomal recessive retinitis pigmentosa (arRP) is a genetically heterogeneous disease resulting in progressive loss of photoreceptors that leads to blindness. To date, 36 genes are known to cause arRP, rendering the molecular diagnosis a challenge. The aim of this study was to use homozygosity mapping to identify the causative mutation in a series of inbred families with arRP. METHODS: arRP patients underwent standard ophthalmic examination, Goldman perimetry, fundus examination, retinal OCT, autofluorescence measurement, and full-field electroretinogram. Fifteen consanguineous families with arRP excluded for USH2A and EYS were genotyped on 250 K SNP arrays. Homozygous regions were listed, and known genes within these regions were PCR sequenced. Familial segregation and mutation analyzes were performed. RESULTS: We found ten mutations, seven of which were novel mutations in eight known genes, including RP1, IMPG2, NR2E3, PDE6A, PDE6B, RLBP1, CNGB1, and C2ORF71, in ten out of 15 families. The patients carrying RP1, C2ORF71, and IMPG2 mutations presented with severe RP, while those with PDE6A, PDE6B, and CNGB1 mutations were less severely affected. The five families without mutations in known genes could be a source of identification of novel genes. CONCLUSIONS: Homozygosity mapping combined with systematic screening of known genes results in a positive molecular diagnosis in 66.7% of families.
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