| 1. |
- Casey, Jillian P, et al.
(författare)
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A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.
- 2012
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 131:4, s. 565-579
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Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
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| 2. |
- Denver, Dee R, et al.
(författare)
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Selective sweeps and parallel mutation in the adaptive recovery from deleterious mutation in Caenorhabditis elegans.
- 2010
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 20:12
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Tidskriftsartikel (refereegranskat)abstract
- Deleterious mutation poses a serious threat to human health and the persistence of small populations. Although adaptive recovery from deleterious mutation has been well-characterized in prokaryotes, the evolutionary mechanisms by which multicellular eukaryotes recover from deleterious mutation remain unknown. We applied high-throughput DNA sequencing to characterize genomic divergence patterns associated with the adaptive recovery from deleterious mutation using a Caenorhabditis elegans recovery-line system. The C. elegans recovery lines were initiated from a low-fitness mutation-accumulation (MA) line progenitor and allowed to independently evolve in large populations (N ∼ 1000) for 60 generations. All lines rapidly regained levels of fitness similar to the wild-type (N2) MA line progenitor. Although there was a near-zero probability of a single mutation fixing due to genetic drift during the recovery experiment, we observed 28 fixed mutations. Cross-generational analysis showed that all mutations went from undetectable population-level frequencies to a fixed state in 10-20 generations. Many recovery-line mutations fixed at identical timepoints, suggesting that the mutations, if not beneficial, hitchhiked to fixation during selective sweep events observed in the recovery lines. No MA line mutation reversions were detected. Parallel mutation fixation was observed for two sites in two independent recovery lines. Analysis using a C. elegans interactome map revealed many predicted interactions between genes with recovery line-specific mutations and genes with previously accumulated MA line mutations. Our study suggests that recovery-line mutations identified in both coding and noncoding genomic regions might have beneficial effects associated with compensatory epistatic interactions.
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| 3. |
- Estes, Suzanne, et al.
(författare)
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Evolutionary codependency : insights into the mitonuclear interaction landscape from experimental and wild Caenorhabditis nematodes
- 2023
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Ingår i: Current Opinion in Genetics and Development. - : Elsevier BV. - 0959-437X .- 1879-0380. ; 81
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Tidskriftsartikel (refereegranskat)abstract
- Aided by new technologies, the upsurgence of research into mitochondrial genome biology during the past 15 years suggests that we have misunderstood, and perhaps dramatically underestimated, the ongoing biological and evolutionary significance of our long-time symbiotic partner. While we have begun to scratch the surface of several topics, many questions regarding the nature of mutation and selection in the mitochondrial genome, and the nature of its relationship to the nuclear genome, remain unanswered. Although best known for their contributions to studies of developmental and aging biology, Caenorhabditis nematodes are increasingly recognized as excellent model systems to advance understanding in these areas. We review recent discoveries with relevance to mitonuclear coevolution and conflict and offer several fertile areas for future work.
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