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  • Review Article
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Relatedness in the post-genomic era: is it still useful?

Nature Reviews Genetics volume 16, pages 33–44 (2015)Cite this article

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Key Points

  • Relatedness is a fundamental concept in everyday life and in quantitative genetics. It has a central role in efforts to understand genetic mechanisms and in predicting phenotypes, as well as in population, evolutionary and forensic genetics.

  • Traditionally, the relatedness of two individuals was measured in terms of the fraction of genome they share IBD (identity-by-descent), which is defined as inheritance from a recent common ancestor, but there are many approaches to interpreting 'recent'.

  • A better viewpoint is given by coalescent theory: the time since the most recent common ancestor for two individuals varies along the genome and can take an essentially continuous range of possible values.

  • There are now many different ways to measure the genetic similarity between pairs of individuals using genome-wide single-nucleotide polymorphism (SNP) data. The binary IBD versus non-IBD distinction provides a simple approximation but gives an inadequate representation of reality compared with the precision offered by the extensive data sets available nowadays.

  • We argue that, for many applications, traditional concepts of relatedness are no longer required; instead, models and analyses can be based directly on genome similarity.

  • There is no one best measure of genome similarity, but different measures can be evaluated on their performance in specific applications.

Abstract

Relatedness is a fundamental concept in genetics but is surprisingly hard to define in a rigorous yet useful way. Traditional relatedness coefficients specify expected genome sharing between individuals in pedigrees, but actual genome sharing can differ considerably from these expected values, which in any case vary according to the pedigree that happens to be available. Nowadays, we can measure genome sharing directly from genome-wide single-nucleotide polymorphism (SNP) data; however, there are many such measures in current use, and we lack good criteria for choosing among them. Here, we review SNP-based measures of relatedness and criteria for comparing them. We discuss how useful pedigree-based concepts remain today and highlight opportunities for further advances in quantitative genetics, with a focus on heritability estimation and phenotype prediction.

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Figure 1: Estimation of narrow-sense heritability (h2) using either expected IBD (θ) or realized IBD (θ′) for varying levels of relatedness.
Figure 2: Statistics of IBD genomic regions.
Figure 3: Heritability estimates (ĥ2) and predictive accuracy (r2) for 139 mouse phenotypes using different SNP-based GSMs.

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Acknowledgements

The authors thank G. Hellenthal and D. Kennett (both University College London), and M. Beaumont (University of Bristol) for discussion. This work is funded by the UK Medical Research Council under grant G0901388, with support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Access to Wellcome Trust Case Control Consortium data was authorized as work related to the project “Genome-wide association study of susceptibility and clinical phenotypes in epilepsy”.

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  1. David J. Balding

    Present address: Present address: Department of Genetics and Department of Mathematics and Statistics, University of Melbourne, Parkville VIC 3010, Australia.,

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  1. UCL Genetics Institute, University College London, Darwin Building, Gower Street, WC1E 6BT, London, UK

    Doug Speed & David J. Balding

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PowerPoint slides

Supplementary information

Supplementary information S1 (Box)

Details of simulations (PDF 133 kb)

Supplementary information S2 (Box)

DNA and pedigree ancestors (PDF 120 kb)

Supplementary information S3 (Box)

Estimating effective population size (PDF 78 kb)

Supplementary information S4 (Box)

Pedigrees generate genome-wide dependence among coalescent trees (PDF 102 kb)

Supplementary information S5 (Box)

Expected IBD region length and expected number of regions shared IBD (PDF 92 kb)

Supplementary information S6 (Box)

Probability that IBD implies IBS (PDF 87 kb)

Supplementary information S7 (Box)

Mixed model likelihood (PDF 92 kb)

Supplementary information S8 (Box)

Inferring the power parameter α (PDF 142 kb)

Glossary

Relatedness

Two individuals are related if they have a recent common ancestor, where 'recent' can be variously defined as outlined under IBD (identity-by-descent).

IBD

(Identity-by-descent; also identical-by-descent). The phenomenon whereby two individuals share a genomic region as a result of inheritance from a recent common ancestor, where 'recent' can mean from an ancestor in a given pedigree, or with no intervening mutation event or with no intervening recombination event.

Pedigree

A set of individuals connected by parent–child relationships.

Most recent common ancestor

(MRCA). Although the ancestries of two alleles may both pass through the same individual, they pass through different alleles with probability 0.5, in which case that individual is not the MRCA of the alleles.

Time since the MRCA

(TMRCA; in generations). If the times back to a common ancestor differ between two individuals, then the average is used.

Heritability

The proportion of phenotypic variation that can be attributed to any genetic variation (broad-sense heritability) or to additive genetic variation (narrow-sense heritability (h2)).

Lineage paths

Sequences of parent–child steps linking individuals with length equal to the number of steps.

Coancestry

(θ). A kinship coefficient defined as the probability that two homologous alleles, one drawn from each of two individuals, are IBD (identical-by-descent).

Inbreeding coefficients

The coancestries of the two parents of an individual.

Maximum likelihood estimators

Estimates of unknown parameters obtained by maximizing the likelihood for the observed data given a statistical model.

Method of moments estimators

Estimates of unknown parameters obtained by equating theoretical moments (for example, mean, variance and skewness) under the assumed statistical model to empirical moments calculated from the observed data.

Coalescent tree

Each leaf of the tree corresponds to an observed allele, and the root represents the most recent common ancestor (MRCA) of all observed alleles. The internal nodes (branching points) represent the MRCA of the alleles at the leaves connected to that node (without passing the root). Distances along branches represent time, measured in generations.

IBS

(Identical-by-state; also identity-by-state). When two homologous alleles have matching type. Some definitions of IBS exclude IBD (identity-by-descent).

Linkage disequilibrium

(LD). A population correlation of allele pairs drawn at different genomic loci in the same gamete (that is, in a haploid genome).

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Speed, D., Balding, D. Relatedness in the post-genomic era: is it still useful?. Nat Rev Genet 16, 33–44 (2015). https://doi.org/10.1038/nrg3821

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