Table 2.
Important genome-wide studies examining de novo variation across a generationa
| Study | Families | Phenotypeb | Technologyc | DNM rate (events/generation)d | Paternal age effecte | Maternal age effecte |
|---|---|---|---|---|---|---|
| Sebat et al. 2007 Science (105) | 264 | ASD | CMA | 0.01 CNVsf | – | – |
| Itsara et al. 2010 Genome Res. (107) | 2197 | ASD | CMA | Varies by sizeg | – | – |
| Roach et al. 2010 Science (81) | 1 | See noteh | WGS | 70 SNVs | – | – |
| Conrad et al. 2011 Nat. Genet. (80) | 2 | NA | WGS | 42 SNVs | – | – |
| Michaelson et al. 2012 Cell (82) | 10 | ASD | WGS | 58 SNVs | 1.0 SNVs | – |
| Kong et al. 2012 Nature (83) | 78 | ASD, SCZ | WGS | 63 SNVs | 2.0 SNVs | – |
| Campbell et al. 2012 Nat. Genet. (84) | 5 | NA | WGS | 35 SNVsi | – | – |
| Gilissen et al. 2014 Nature (85) | 50 | ID | WGS | 82 SNVs, 0.16 CNVs | – | – |
| Francioli et al. 2014, 2015 Nat. Genet. (86,87) | 250 | NA | WGS | 43 SNVs | 1.1 SNVs | – |
| Wong et al. 2016 Nat. Commun. (88) | 693 | PTB | WGS | 39 SNVs | 0.64 SNVs | 0.35 SNVs |
| Goldmann et al. 2016 Nat. Genet. (89) | 816 | PTB | WGS | 45 SNVs | 0.91 SNVs | 0.24 SNVs |
| Yuen et al. 2016 NPJ Genom. Med. (90) | 200 | ASD | WGS | 51 SNVs, 4 indels, 0.05 CNVsj | – | – |
| Yuen et al. 2017 Nat. Neurosci. (91) | 1239 | ASD | WGS | 74 SNVs, 13 indels | – | – |
| Jónsson et al. 2017 Nature (92) | 1548 | Various | WGS | 65 SNVs, 5 indels | 1.51 SNVs+indels | 0.37 SNVs+indels |
| Maretty et al. 2017 Nature (93) | 50 | NA | WGS | 64 SNVs, 6 indels | – | – |
| An et al. 2018 Science (95) | 1902 | ASD | WGS | 62 SNVs, 6 indels | – | – |
| Kessler et al. 2020 Proc. Natl. Acad. Sci. (94) | 1465 | Various | WGS | 64 SNVs | 1.35 SNVs | 0.42 SNVs |
| Collins et al. 2020 Nature (109) | 970 | Various | WGS | 0.29 SVsk | – | – |
| Belyeu et al. 2021 Am. J. Hum. Genet. (110) | 2396 | ASD | WGS | 0.16 SVsl | Not significant | Not significant |
| Mitra et al. 2021 Nature (103) | 1637 | ASD | WGS | 53 tandem repeat indelsm | Significantn | – |
We selected studies that tested for genome-wide de novo mutation events from population control or disease datasets. Each study has strengths and weaknesses in design, data capture and experimental validation. Four comprehensive studies (90–93) report an average of 64 SNV, 7 indel and 0.05 CNV events per generation.
The phenotype or disease of participants in the study. ‘NA’ means that only healthy controls were used or that no disease phenotype was indicated. ASD, autism spectrum disorder; ID, intellectual disability; PTB, preterm birth; SCZ, schizophrenia.
The technology used for variant detection. CMA, chromosomal microarray analysis; WGS, whole-genome sequencing.
DNM rates are reported in terms of events per generation because this measure is generalizable across variant types (i.e. also including indels and SVs). As mentioned in the text, after adjusting for the proportion of the genome assessed, estimates of per-nucleotide mutation rates for de novo SNVs are consistently reported as ~1.2 × 10−8 per generation.
The estimated number of additional de novo variants per year of parental age.
CNVs > 99 kb in unaffected individuals only.
CNVs > 30 kb: 0.012; CNVs > 500 kb: 0.0065.
The two siblings in this study each had two recessive disorders.
This study also estimated mutation rates based on heterozygous positions within autozygous segments, giving a per-nucleotide mutation rate of 1.2 × 10−8 per generation.
CNVs > 10 kb.
Includes 0.15 deletions, 0.1 insertions, 0.04 duplications and 0.001 inversions.
Value is for healthy individuals; DNM rate was significantly higher in ASD-affected individuals (0.21 SVs/generation).
Value is for healthy individuals; DNM rate was slightly but significantly higher in ASD-affected individuals (55 tandem repeat indels/generation).
Paternal age effect was statistically significant, but no slope given.