Hotspots of Human Mutation

Nesta, Alex; Tafur, Denisse; Beck, Christine R.

doi:10.1016/j.tig.2020.10.003

Cited by 90 publications

(66 citation statements)

References 135 publications

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“…Furthermore, specific DNA structures can make DNA sequences more vulnerable to alteration. The DNA repair system can also be weakened in some sequence regions [ 26 ]. The exact mechanism for the occurrence of these hotspot positions in ALOX12B and ALOXE3 is still unknown.…”

Section: Discussionmentioning

confidence: 99%

Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients

Hotz

Köpp

Bourrat

et al. 2021

Genes

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The autosomal recessive congenital ichthyoses (ARCI) are a nonsyndromic group of cornification disorders that includes lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. To date mutations in ten genes have been identified to cause ARCI: TGM1, ALOX12B, ALOXE3, NIPAL4, CYP4F22, ABCA12, PNPLA1, CERS3, SDR9C7, and SULT2B1. The main focus of this report is the mutational spectrum of the genes ALOX12B and ALOXE3, which encode the epidermal lipoxygenases arachidonate 12-lipoxygenase, i.e., 12R type (12R-LOX), and the epidermis-type lipoxygenase-3 (eLOX3), respectively. Deficiency of 12R-LOX and eLOX3 disrupts the epidermal barrier function and leads to an abnormal epidermal differentiation. The type and the position of the mutations may influence the ARCI phenotype; most patients present with a mild erythrodermic ichthyosis, and only few individuals show severe erythroderma. To date, 88 pathogenic mutations in ALOX12B and 27 pathogenic mutations in ALOXE3 have been reported in the literature. Here, we presented a large cohort of 224 genetically characterized ARCI patients who carried mutations in these genes. We added 74 novel mutations in ALOX12B and 25 novel mutations in ALOXE3. We investigated the spectrum of mutations in ALOX12B and ALOXE3 in our cohort and additionally in the published mutations, the distribution of these mutations within the gene and gene domains, and potential hotspots and recurrent mutations.

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Section: Discussionmentioning

confidence: 99%

Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients

Hotz

Köpp

Bourrat

et al. 2021

Genes

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“…Moreover, because the tree sequence approach captures the structure of human relationships and genomic diversity, it provides a principled basis for combining data from multiple different sources, enabling tasks such as imputing missing data and identifying (and correcting) sporadic and systematic errors in the underlying data. Our results identified different types of error common in reference data sets (erroneous sites and genotyping error) as well as emphasising the importance of recurrent mutation in generating human genetic diversity 61,62 . Although additional work is required to correct such errors, as well as integrate other types of mutation, notably structural variation, a reference tree sequence for human variation -along with the tools to use it appropriately 10,25 -potentially represents a basis for harmonising a much larger and wider set of genomic data sources and enabling cross data-source analyses.…”

Section: Discussionmentioning

confidence: 67%

A unified genealogy of modern and ancient genomes

Wohns

Wong

Jeffery

et al. 2021

Preprint

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The sequencing of modern and ancient genomes from around the world has revolutionised our understanding of human history and evolution. However, the general problem of how best to characterise the full complexity of ancestral relationships from the totality of human genomic variation remains unsolved. Patterns of variation in each data set are typically analysed independently, and often using parametric models or data reduction techniques that cannot capture the full complexity of human ancestry. Moreover, variation in sequencing technology, data quality and in silico processing, coupled with complexities of data scale, limit the ability to integrate data sources. Here, we introduce a non-parametric approach to inferring human genealogical history that overcomes many of these challenges and enables us to build the largest genealogy of both modern and ancient humans yet constructed. The genealogy provides a lossless and compact representation of multiple datasets, addresses the challenges of missing and erroneous data, and benefits from using ancient samples to constrain and date relationships. Using simulations and empirical analyses, we demonstrate the power of the method to recover relationships between individuals and populations, as well as to identify descendants of ancient samples. Finally, we show how applying a simple nonparametric estimator of ancestor geographical location to the inferred genealogy recapitulates key events in human history. Our results demonstrate that whole-genome genealogies are a powerful means of synthesising genetic data and provide rich insights into human evolution.

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“…We compared the accessibilities of all regions of 10 nt length, and found distinct differences at 3 regions of exon 1. Furthermore, we used RNAup -b [24] to compare possible interactions in homodimeric and heterodimeric SBF1 rst exon with different numbers of (GCC)-repeats.…”

Section: Structural Analysis Of the Human Sbf1 With Different Numbers Of (Gcc)-repeatsmentioning

confidence: 99%

A (GCC) Repeat in the Untranslated Region of Human SBF1 Departs from Hardy-Weinberg Equilibrium in Human and Links to Late-onset Neurocognitive Disorder.

Ohadi

Khamse

Alizadeh

et al. 2022

Preprint

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The human SBF1 (SET binding factor 1) gene, alternatively known as MTMR5, is predominantly expressed in the brain, and its epigenetic dysregulation is linked to late-onset neurocognitive disorders (NCDs), such as Alzheimer’s disease. This gene contains a (GCC)-repeat at the interval between +1 and +60 of the transcription start site (SBF1-202 ENST00000380817.8). Sequencing of the SBF1 (GCC)-repeat in a sample of 542 Iranian individuals, consisting of late-onset NCDs (N=260) and controls (N=282) revealed a predominantly bi-allelic locus for this STR, consisting of 8 and 9 repeats, with allele frequencies ranging from 0.39 to 0.55, and four other alleles with frequencies of <0.03 across the two groups. Overall heterozygosity for the observed alleles was significantly less than expected in the NCD and control groups, at 22.3% and 16.31%, respectively (p=0.000). Specifically, the heterozygous 8/9 genotype was significantly less than expected in both case and control groups (Hardy-Weinberg disequilibrium, p=0.000), and significantly enriched in the NCD group (Yates corrected p=0.001). Skewed heterozygous genotypes were also detected for other allele combinations, such as 6/8 vs 6/9 across groups (p=0.000). Bioinformatics studies revealed that the number of (GCC)-repeats may change the RNA secondary structure and interaction sites across human exon 1. This STR was specifically expanded beyond 2-repeats in primates. In conclusion, we report a novel biological phenomenon in which there is indication of purifying selection against heterozygous genotypes at a STR locus in human, and skewed genotype compartment in late-onset NCD vs. controls. In view of the location of this STR in the 5′ UTR, RNA/RNA or RNA/DNA heterodimer formation of the involved genotypes and possible deleterious downstream events should be considered.

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Hotspots of Human Mutation

Cited by 90 publications

References 135 publications

Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients

Meta-Analysis of Mutations in ALOX12B or ALOXE3 Identified in a Large Cohort of 224 Patients

A unified genealogy of modern and ancient genomes

A (GCC) Repeat in the Untranslated Region of Human SBF1 Departs from Hardy-Weinberg Equilibrium in Human and Links to Late-onset Neurocognitive Disorder.

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