Whole-Genome Sequencing in Autism Identifies Hot Spots for De Novo Germline Mutation

Michaelson, Jacob J.; Shi, Yujian; Gujral, Madhusudan; Zheng, Hancheng; Malhotra, Dheeraj; Jin, Xin; Jian, Minghan; Liu, Guangming; Greer, Douglas S.; Bhandari, Abhishek; Wu, Wenting; Corominas, Roser; Peoples, Áine; Koren, Amnon; Gore, Athurva; Kang, Shuli; Lin, Guan Ning; Estabillo, Jasper A.; Gadomski, Therese; Singh, Balvindar; Zhang, Kun; Akshoomoff, Natacha; Corsello, Christina; McCarroll, Steven A.; Iakoucheva, Lilia M.; Li, Yingrui; Wang, Jun; Sebat, Jonathan

doi:10.1016/j.cell.2012.11.019

Cited by 494 publications

(583 citation statements)

References 62 publications

Supporting

Mentioning

511

Contrasting

Unclassified

Order By: Relevance

“…The mutation spectrum thus resembles that of mutations that occurred in germ cells and persisted in the offspring population, often with no pathogenic effects (dbSNP) but distinctly different from that of diseaseassociated mutations (ClinVar). These results are in agreement with recent findings that chromatin organization influences the genomic susceptibility to acquire somatic mutations (Michaelson et al 2012;Schuster-Bockler and Lehner 2012).…”

Section: Somatic Mutations Routinely Occur In the Blood Genomesupporting

confidence: 83%

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis

et al. 2014

View full text Add to dashboard Cite

The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole-genome sequencing, we estimate that approximately 450 somatic mutations accumulated in the nonrepetitive genome within the healthy blood compartment of a 115-yr-old woman. The detected mutations appear to have been harmless passenger mutations: They were enriched in noncoding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes. The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.

show abstract

Section: Somatic Mutations Routinely Occur In the Blood Genomesupporting

confidence: 83%

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis

et al. 2014

View full text Add to dashboard Cite

show abstract

“…This mutation rate is supported by many previous wholegenome studies ( [51,[78][79][80][81]; range: 1 − 1.2 Ã 10 −8 mutations / basepair / generation), but we are aware of recent studies suggesting a higher mutation rate that are either based on exome data ( [82][83][84]; range: 1.3 − 2.2 Ã 10 −8 mutations / basepair / generation) or whole-genome data ( [85,86]; range: 1.61 − 1.66 Ã 10 −8 mutations / basepair / generation). To take into account this uncertainty, we performed additional analyses using a mutation rate of 1.6 Ã 10 −8 mutations / basepair / generation.…”

Section: Scaling Parameter Uncertaintysupporting

confidence: 64%

Population Genetic Analysis of the DARC Locus (Duffy) Reveals Adaptation from Standing Variation Associated with Malaria Resistance in Humans

McManus

Taravella

Henn

et al. 2016

Preprint

View full text Add to dashboard Cite

The human DARC (Duffy antigen receptor for chemokines) gene encodes a membranebound chemokine receptor crucial for the infection of red blood cells by Plasmodium vivax, a major causative agent of malaria. Of the three major allelic classes segregating in human populations, the FY*O allele has been shown to protect against P. vivax infection and is at near fixation in sub-Saharan Africa, while FY*B and FY*A are common in Europe and Asia, respectively. Due to the combination of strong geographic differentiation and association with malaria resistance, DARC is considered a canonical example of positive selection in humans. Despite this, details of the timing and mode of selection at DARC remain poorly understood. Here, we use sequencing data from over 1,000 individuals in twenty-one human populations, as well as ancient human genomes, to perform a fine-scale investigation of the evolutionary history of DARC. We estimate the time to most recent common ancestor (T MRCA ) of the most common FY*O haplotype to be 42 kya (95% CI: 34-49 kya). We infer the FY*O null mutation swept to fixation in Africa from standing variation with very low initial frequency (0.1%) and a selection coefficient of 0.043 (95% CI:0.011-0.18), which is among the strongest estimated in the human genome. We estimate the T MRCA of the FY*A mutation in non-Africans to be 57 kya (95% CI: 48-65 kya) and infer that, prior to the sweep of FY*O, all three alleles were segregating in Africa, as highly diverged populations from Asia and 6 ¼Khomani San hunter-gatherers share the same FY*A haplotypes. We test multiple models of admixture that may account for this observation and reject recent Asian or European admixture as the cause.

show abstract

“…Moreover, a combination of signatures 1 and 5 also recapitulates the pattern of de novo mutations found in the human germline (data from refs. [12][13][14], and this de novo germline pattern cannot be parsimoniously generated by other combinations of known mutational signatures (Supplementary Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Clock-like mutational processes in human somatic cells

et al. 2015

View full text Add to dashboard Cite

During the course of a lifetime somatic cells acquire mutations. Different mutational processes may contribute to the mutations accumulated in a cell, with each imprinting a mutational signature on the cell's genome. Some processes generate mutations throughout life at a constant rate in all individuals and the number of mutations in a cell attributable to these processes will be proportional to the chronological age of the person. Using mutations from 10,250 cancer genomes across 36 cancer types, we investigated clock-like mutational processes that have been operating in normal human cells. Two mutational signatures show clock-like properties. Both exhibit different mutation rates in different tissues. However, their mutation rates are not correlated indicating that the underlying processes are subject to different biological influences. For one signature, the rate of cell division may influence its mutation rate. This study provides the first survey of clock-like mutational processes operative in human somatic cells.

show abstract

Whole-Genome Sequencing in Autism Identifies Hot Spots for De Novo Germline Mutation

Cited by 494 publications

References 62 publications

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis

Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis

Population Genetic Analysis of the DARC Locus (Duffy) Reveals Adaptation from Standing Variation Associated with Malaria Resistance in Humans

Clock-like mutational processes in human somatic cells

Contact Info

Product

Resources

About