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- Hu, H., et al.
(författare)
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X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes
- 2016
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 21:1, s. 133-148
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Tidskriftsartikel (refereegranskat)abstract
- X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.
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| 2. |
- Erlichman, Adèle, et al.
(författare)
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Planting long-lived trees in a warming climate : Theory shows the importance of stage-dependent climatic tolerance
- 2024
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Ingår i: Evolutionary Applications. - : John Wiley & Sons. - 1752-4571. ; 17:6
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Tidskriftsartikel (refereegranskat)abstract
- Climate change poses a particular threat to long-lived trees, which may not adapt or migrate fast enough to keep up with rising temperatures. Assisted gene flow could facilitate adaptation of populations to future climates by using managed translocation of seeds from a warmer location (provenance) within the current range of a species. Finding the provenance that will perform best in terms of survival or growth is complicated by a trade-off. Because trees face a rapidly changing climate during their long lives, the alleles that confer optimal performance may vary across their lifespan. For instance, trees from warmer provenances could be well adapted as adults but suffer from colder temperatures while juvenile. Here we use a stage-structured model, using both analytical predictions and numerical simulations, to determine which provenance would maximize the survival of a cohort of long-lived trees in a changing climate. We parameterize our simulations using empirically estimated demographic transition matrices for 20 long-lived tree species. Unable to find reliable quantitative estimates of how climatic tolerance changes across stages in these same species, we varied this parameter to study its effect. Both our mathematical model and simulations predict that the best provenance depends strongly on how fast the climate changes and also how climatic tolerance varies across the lifespan of a tree. We thus call for increased empirical efforts to measure how climate tolerance changes over life in long-lived species, as our model suggests that it should strongly influence the best provenance for assisted gene flow.
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