Dataset Information

Quantifying the contribution of recessive coding variation to developmental disorders.

ABSTRACT: We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.

SUBMITTER: Martin HC

PROVIDER: S-EPMC6726470 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Quantifying the contribution of recessive coding variation to developmental disorders.

Martin Hilary C HC Jones Wendy D WD McIntyre Rebecca R Sanchez-Andrade Gabriela G Sanderson Mark M Stephenson James D JD Jones Carla P CP Handsaker Juliet J Gallone Giuseppe G Bruntraeger Michaela M McRae Jeremy F JF Prigmore Elena E Short Patrick P Niemi Mari M Kaplanis Joanna J Radford Elizabeth J EJ Radford Elizabeth J EJ Akawi Nadia N Balasubramanian Meena M Dean John J Horton Rachel R Hulbert Alice A Johnson Diana S DS Johnson Katie K Kumar Dhavendra D Lynch Sally Ann SA Mehta Sarju G SG Morton Jenny J Parker Michael J MJ Splitt Miranda M Turnpenny Peter D PD Vasudevan Pradeep C PC Wright Michael M Bassett Andrew A Gerety Sebastian S SS Wright Caroline F CF FitzPatrick David R DR Firth Helen V HV Hurles Matthew E ME Barrett Jeffrey C JC

Science (New York, N.Y.) 20181108 6419

We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously ass ...[more]

PMID: 30409806

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Project description:Genotypic variation, environmental variation, and their interaction may produce variation in the developmental process and cause phenotypic differences among individuals. Developmental noise, which arises during development from stochasticity in cellular and molecular processes when genotype and environment are fixed, also contributes to phenotypic variation. While evolutionary biology has long focused on teasing apart the relative contribution of genes and environment to phenotypic variation, our understanding of the role of developmental noise has lagged due to technical difficulties in directly measuring the contribution of developmental noise. The influence of developmental noise is likely underestimated in studies of phenotypic variation due to intrinsic mechanisms within organisms that stabilize phenotypes and decrease variation. Since we are just beginning to appreciate the extent to which phenotypic variation due to stochasticity is potentially adaptive, the contribution of developmental noise to phenotypic variation must be separated and measured to fully understand its role in evolution. Here, we show that variation in the component of the developmental process corresponding to environmental and genetic factors (here treated together as a unit called the LALI-type) versus the contribution of developmental noise, can be distinguished for leopard gecko (Eublepharis macularius) head color patterns using mathematical simulations that model the role of random variation (corresponding to developmental noise) in patterning. Specifically, we modified the parameters of simulations corresponding to variation in the LALI-type to generate the full range of phenotypic variation in color pattern seen on the heads of eight leopard geckos. We observed that over the range of these parameters, variation in color pattern due to LALI-type variation exceeds that due to developmental noise in the studied gecko cohort. However, the effect of developmental noise on patterning is also substantial. Our approach addresses one of the major goals of evolutionary biology: to quantify the role of stochasticity in shaping phenotypic variation.

Dataset Information

Quantifying the contribution of recessive coding variation to developmental disorders.

Publications

Quantifying the contribution of recessive coding variation to developmental disorders.

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