| 1. |
- Gao, Hong, et al.
(författare)
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The landscape of tolerated genetic variation in humans and primates
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6648
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Tidskriftsartikel (refereegranskat)abstract
- Personalized genome sequencing has revealed millions of genetic differences between individuals, but our understanding of their clinical relevance remains largely incomplete. To systematically decipher the effects of human genetic variants, we obtained whole-genome sequencing data for 809 individuals from 233 primate species and identified 4.3 million common protein-altering variants with orthologs in humans. We show that these variants can be inferred to have nondeleterious effects in humans based on their presence at high allele frequencies in other primate populations. We use this resource to classify 6% of all possible human protein-altering variants as likely benign and impute the pathogenicity of the remaining 94% of variants with deep learning, achieving state-of-the-art accuracy for diagnosing pathogenic variants in patients with genetic diseases.
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| 2. |
- Kruskopf Österberg, Marita, 1970-
(författare)
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From QTLs to Genes: Flowering Time Variation and CONSTANS-LIKE Genes in the Black Mustard (Brassica nigra)
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The transition to flowering is a major developmental switch in angiosperms, the timing of which is expected to be important for fitness. In this thesis the focus has been on identification of genes affecting natural variation in flowering time in Brassica nigra. The background for this thesis is an earlier QTL-mapping study in B. nigra. The genomic area with the greatest effect on flowering time in that study contained a homolog to the CONSTANS gene, which is known to affect flowering time in A. thaliana. When studied more closely this gene did not seem to affect flowering time variation in B. nigra. Near the B.nigra CO gene (BniCOa), however, we identified a homolog to the related CONSTANS LIKE 1 (COL1) gene. In A. thaliana COL1 has not been shown to be associated with induction of flowering but since the B. nigra homolog (BniCOL1) in the QTL area showed surprising amounts of variation between early and late flowering plants we set out to test if this variation was associated with flowering time variation. In the first paper we found a significant association between flowering time and one indel (Ind2) in the coding region. Motivated by the results in paper one, we searched for evidence of selection at the BniCOL1(paper two). In paper three the aim was to validate the results from the first paper in a larger sample of populations, and to check whether the association found in paper I could reflect linkage disequilibrium with areas outside of the gene. Finally, in paper four we investigate the general evolution of three CONSTANS-LIKE genes in B. nigra, namely BniCOL1, BniCOa and BniCOb.
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| 3. |
- Kuderna, Lukas F. K., et al.
(författare)
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A global catalog of whole-genome diversity from 233 primate species
- 2023
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6648, s. 906-913
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Tidskriftsartikel (refereegranskat)abstract
- The rich diversity of morphology and behavior displayed across primate species provides an informative context in which to study the impact of genomic diversity on fundamental biological processes. Analysis of that diversity provides insight into long-standing questions in evolutionary and conservation biology and is urgent given severe threats these species are facing. Here, we present high-coverage wholegenome data from 233 primate species representing 86% of genera and all 16 families. This dataset was used, together with fossil calibration, to create a nuclear DNA phylogeny and to reassess evolutionary divergence times among primate clades. We found within-species genetic diversity across families and geographic regions to be associated with climate and sociality, but not with extinction risk. Furthermore, mutation rates differ across species, potentially influenced by effective population sizes. Lastly, we identified extensive recurrence of missense mutations previously thought to be human specific. This study will open a wide range of research avenues for future primate genomic research.
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| 4. |
- Kuderna, Lukas F. K., et al.
(författare)
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Identification of constrained sequence elements across 239 primate genomes
- 2024
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 625:7996, s. 735-742
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Tidskriftsartikel (refereegranskat)abstract
- Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3,4,5,6,7,8,9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.
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