A DNA segment is identical by state (IBS) in two or more individuals if they have identical nucleotide sequences in this segment. An IBS segment is identical by descent (IBD) in two or more individuals if they have inherited it from a common ancestor without recombination, that is, the segment has the same ancestral origin in these individuals. DNA segments that are IBD are IBS per definition, but segments that are not IBD can still be IBS due to the same

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

s in different individuals or recombinations that do not alter the segment.

Theory

All individuals in a finite population are related if traced back long enough and will, therefore, share segments of their

genomes In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ...

IBD. During

meiosis Meiosis (; , since it is a reductional division) is a special type of cell division of germ cells in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately r ...

segments of IBD are broken up by recombination. Therefore, the expected length of an IBD segment depends on the number of generations since the

most recent common ancestor In biology and genetic genealogy, the most recent common ancestor (MRCA), also known as the last common ancestor (LCA) or concestor, of a set of organisms is the most recent individual from which all the organisms of the set are descended. The ...

at the locus of the segment. The length of IBD segments that result from a common ancestor ''n'' generations in the past (therefore involving 2''n'' meiosis) is exponentially distributed with mean 1/(2''n'') Morgans (M). The expected number of IBD segments decreases with the number of generations since the common ancestor at this locus. For a specific DNA segment, the probability of being IBD decreases as 2^−2''n'' since in each meiosis the probability of transmitting this segment is 1/2.

Applications

Identified IBD segments can be used for a wide range of purposes. As noted above the amount (length and number) of IBD sharing depends on the familial relationships between the tested individuals. Therefore, one application of IBD segment detection is to quantify relatedness. Measurement of relatedness can be used in forensic genetics, but can also increase information in

genetic linkage Genetic linkage is the tendency of DNA sequences that are close together on a chromosome to be inherited together during the meiosis phase of sexual reproduction. Two genetic markers that are physically near to each other are unlikely to be sep ...

mapping and help to decrease

bias Bias is a disproportionate weight ''in favor of'' or ''against'' an idea or thing, usually in a way that is closed-minded, prejudicial, or unfair. Biases can be innate or learned. People may develop biases for or against an individual, a group ...

by undocumented relationships in standard association studies. Another application of IBD is genotype imputation and

haplotype A haplotype (haploid genotype) is a group of alleles in an organism that are inherited together from a single parent. Many organisms contain genetic material ( DNA) which is inherited from two parents. Normally these organisms have their DNA org ...

phase Phase or phases may refer to: Science *State of matter, or phase, one of the distinct forms in which matter can exist *Phase (matter), a region of space throughout which all physical properties are essentially uniform *Phase space, a mathematica ...

inference. Long shared segments of IBD, which are broken up by short regions may be indicative for phasing errors.

IBD mapping

IBD mapping is similar to linkage analysis, but can be performed without a known pedigree on a cohort of unrelated individuals. IBD mapping can be seen as a new form of association analysis that increases the power to map genes or genomic regions containing multiple rare disease susceptibility variants. Using simulated data, Browning and Thompson showed that IBD mapping has higher power than association testing when multiple rare variants within a gene contribute to disease susceptibility. Via IBD mapping, genome-wide significant regions in isolated populations as well as outbred populations were found while standard association tests failed. Houwen et al. used IBD sharing to identify the chromosomal location of a gene responsible for benign recurrent intrahepatic

cholestasis Cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system that can occur from a gallstone or malignan ...

in an isolated fishing population. Kenny et al. also used an isolated population to fine-map a signal found by a

genome-wide association study In genomics, a genome-wide association study (GWA study, or GWAS), also known as whole genome association study (WGA study, or WGAS), is an observational study of a genome-wide set of genetic variants in different individuals to see if any varian ...

(GWAS) of plasma

plant sterol Phytosterols are phytosteroids, similar to cholesterol, that serve as structural components of biological membranes of plants. They encompass plant sterols and stanols. More than 250 sterols and related compounds have been identified. Free phyto ...

(PPS) levels, a surrogate measure of cholesterol absorption from the intestine. Francks et al. was able to identify a potential susceptibility locus for

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social with ...

and

bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...

with genotype data of case-control samples. Lin et al. found a genome-wide significant linkage signal in a dataset of

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. Thi ...

patients. Letouzé et al. used IBD mapping to look for founder mutations in

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...

samples.

IBD segment detected by HapFABIA in 1000Genomes

IBD in population genetics

Detection of

natural selection Natural selection is the differential survival and reproduction of individuals due to differences in phenotype. It is a key mechanism of evolution, the change in the heritable traits characteristic of a population over generations. Char ...

in the human genome is also possible via detected IBD segments. Selection will usually tend to increase the number of IBD segments among individuals in a population. By scanning for regions with excess IBD sharing, regions in the human genome that have been under strong, very recent selection can be identified. In addition to that, IBD segments can be useful for measuring and identifying other influences on population structure. Gusev et al. showed that IBD segments can be used with additional modeling to estimate demographic history including bottlenecks and admixture. Using similar models Palamara et al. and Carmi et al. reconstructed the

demographic history Demographic history is the reconstructed record of human population in the past. Given the lack of population records prior to the 1950s, there are many gaps in our record of demographic history. Historical demographers must make do with estimates, ...

Ashkenazi Jewish Ashkenazi Jews ( ; he, יְהוּדֵי אַשְׁכְּנַז, translit=Yehudei Ashkenaz, ; yi, אַשכּנזישע ייִדן, Ashkenazishe Yidn), also known as Ashkenazic Jews or ''Ashkenazim'',, Ashkenazi Hebrew pronunciation: , singu ...

and Kenyan

Maasai Maasai may refer to: *Maasai people The Maasai (; sw, Wamasai) are a Nilotic ethnic group inhabiting northern, central and southern Kenya and northern Tanzania. They are among the best-known local populations internationally due to their r ...

individuals. Botigué et al. investigated differences in African ancestry among European populations. Ralph and Coop used IBD detection to quantify the common ancestry of different European populations and Gravel et al. similarly tried to draw conclusions of the genetic history of populations in the Americas. Ringbauer et al. utilized geographic structure of IBD segments to estimate dispersal within Eastern Europe during the last centuries. Using the 1000 Genomes data Hochreiter found differences in IBD sharing between African, Asian and European populations as well as IBD segments that are shared with ancient genomes like the

Neanderthal Neanderthals (, also ''Homo neanderthalensis'' and erroneously ''Homo sapiens neanderthalensis''), also written as Neandertals, are an extinct species or subspecies of archaic humans who lived in Eurasia until about 40,000 years ago. While the ...

or Denisova.

Methods and software

Programs for the detection of IBD segments in unrelated individuals:
RAPID
Ultra-fast Identity by Descent Detection in Biobank-Scale Cohorts using Positional Burrows–Wheeler Transform Naseri A, Liu X, Zhang S, Zhi D. Ultra-fast Identity by Descent Detection in Biobank-Scale Cohorts using Positional Burrows–Wheeler Transform BioRxiv 2017.
Parente
identifies IBD segments between pairs of individuals in unphased genotype dataRodriguez JM, Batzoglou S, Bercovici S. An accurate method for inferring relatedness in large datasets of unphased genotypes via an embedded likelihood-ratio test. RECOMB 2013, LNBI 7821:212-229.

finds segments of IBD between pairs of individuals in genome-wide SNP data
BEAGLE/RefinedIBD
finds IBD segments in pairs of individuals using a hashing method and evaluates their significance via a likelihood ratio

detects pairwise IBD segments in sequencing data
GERMLINE
discovers in linear-time IBD segments in pairs of individuals
DASH
builds upon pairwise IBD segments to infer clusters of individuals likely to be sharing a single haplotype
PLINK
is a tool set for

whole genome association In genomics, a genome-wide association study (GWA study, or GWAS), also known as whole genome association study (WGA study, or WGAS), is an observational study of a genome-wide set of genetic variants in different individuals to see if any varian ...

and population-based linkage analyses including a method for pairwise IBD segment detection
Relate
estimates the probability of IBD between pairs of individuals at a specific locus using SNPs
MCMC_IBDfinder
is based on

Markov chain Monte Carlo In statistics, Markov chain Monte Carlo (MCMC) methods comprise a class of algorithms for sampling from a probability distribution. By constructing a Markov chain that has the desired distribution as its equilibrium distribution, one can obtain ...

(MCMC) for finding IBD segments in multiple individuals
IBD-Groupon
detects group-wise IBD segments based on pairwise IBD relationships
HapFABIA
identifies very short IBD segments characterized by rare variants in large

sequencing In genetics and biochemistry, sequencing means to determine the primary structure (sometimes incorrectly called the primary sequence) of an unbranched biopolymer. Sequencing results in a symbolic linear depiction known as a sequence which suc ...

data simultaneously in multiple individuals

References