Abstract
Runs of homozygosity (ROH) are regions consistently homozygous for genetic markers, which can occur throughout the human genome. Their size is dependent on the degree of shared parental ancestry, being longer in individuals descending from consanguineous marriages, or from inbred/isolated populations. Based on ROH existence, homozygosity mapping (HM) was developed as powerful tool for gene-discovery in human genetics. HM is based on the assumption that, through identity-by-descent, individuals affected by an autosomal recessive (AR) condition, are more likely to have homozygous markers surrounding the disease locus.
In this work, we reviewed some of the algorithms and bioinformatics tools available for HM and ROH detection, with special emphasis on those than can be applied to data from whole-exome sequencing (WES) data. Preliminary data is also shown demonstrating the relevance of performing ROH analysis, especially in sporadic cases. In this study, ROH from WES data of twelve unrelated patients was analyzed. Patients with AR diseases (n = 6) were subdivided into two groups: homozygous and compound heterozygous. ROH analysis was performed using the HomozygosityMapper software, varying the block length and collecting several parameters. Statistically significant differences between the two groups were identified for ROH total size and homozygosity score. The k-means clustering algorithm was then applied, where two clusters were identified, with statistically significant differences, corresponding to each predefined test group. Our results suggest that, in some cases, it may be possible to infer the most likely disease inheritance model from WES data alone, constituting a useful starting point for the subsequent variant filtering strategies.
J. Oliveira and R. Pereira—Equally contributing authors.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Miko, I.: Gregor mendel and the principles of inheritance. Nat. Educ. 1(1), 134 (2008)
Christianson, A., Howson, C.P., Modell, B.: Global report on birth defects: the hidden toll of dying and disabled children, New York (2006)
Lobo, I., Shaw, K.: Discovery and types of genetic linkage. Nat. Educ. 1(1), 139 (2008)
Slatkin, M.: Linkage disequilibrium—understanding the evolutionary past and mapping the medical future. Nat. Rev. Genet. 9(6), 477–485 (2008)
Sanger, F., Nicklen, S., Coulson, A.R.: DNA sequencing with chain-terminating inhibitors. PNAS 74(12), 5463–5467 (1977)
Boycott, K.M., et al.: Rare-disease genetics in the era of next-generation sequencing: discovery to translation. Nat. Rev. Genet. 14(10), 681–691 (2013)
Xia, J., et al.: NGS catalog: a database of next generation sequencing studies in humans. Hum. Mutat. 33(6), E2341–E2355 (2012)
Koboldt, D.C., et al.: The next-generation sequencing revolution and its impact on genomics. Cell 155(1), 27–38 (2013)
Bittles, A.H.: Consanguinity and its relevance to clinical genetics. Clin. Genet. 60(2), 89–98 (2001)
Instituto Nacional de Estatística: Marriages (Between persons of the opposite sex - No.) by Place of registration (NUTS - 2002), Sex, Relationship or affinity between the spouses and Spouse previous marital status; Annual
McQuillan, R., et al.: Runs of homozygosity in European populations. Am. J. Hum. Genet. 83(3), 359–372 (2008)
Lander, E.S., Botstein, D.: Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. Science 236(4808), 1568–1570 (1987)
Alkuraya, F.S.: Autozygome decoded. Genet. Med. 12(12), 765–771 (2010)
Goodship, J., et al.: Report autozygosity mapping of a Seckel syndrome locus to chromosome 3q22.1-q24. Am. J. Hum. Genet. 67, 498–503 (2000)
Alkuraya, F.S.: Homozygosity mapping: one more tool in the clinical geneticist’s toolbox. Genet. Med. 12(4), 236–239 (2010)
Syvänen, A.-C.: Toward genome-wide SNP genotyping. Nat. Genet. 37(6s), S5 (2005)
Gibbs, J.R., Singleton, A.: Application of genome-wide single nucleotide polymorphism typing: simple association and beyond. PLoS Genet. 2(10), e150 (2006)
Evans, D.M., Cardon, L.R.: Guidelines for genotyping in genomewide linkage studies: single-nucleotide–polymorphism maps versus microsatellite maps. Am. J. Hum. Genet. 75(4), 687–692 (2004)
Wang, Z., Gerstein, M., Snyder, M.: RNA-seq: a revolutionary tool for transcriptomics. Nat. Rev. Genet. 10(1), 57–63 (2009)
Park, P.J.: ChIP-seq: advantages and challenges of a maturing technology. Nat. Rev. Genet. 10(10), 669–680 (2009)
Li, Y., Tollefsbol, T.O.: DNA methylation detection: bisulfite genomic sequencing analysis. In: Tollefsbol, T. (ed.) Methods in Molecular Biology, vol. 791, pp. 11–21. Springer, Heidelberg (2011). https://doi.org/10.1007/978-1-61779-316-5_2
Mardis, E.R.: The impact of next-generation sequencing technology on genetics. Trends Genet. 24(3), 133–141 (2008)
Ng, S.B., et al.: Exome sequencing identifies the cause of a mendelian disorder. Nat. Genet. 42(1), 30–35 (2010)
Oliveira, J., et al.: New splicing mutation in the choline kinase beta (CHKB) gene causing a muscular dystrophy detected by whole-exome sequencing. J. Hum. Genet. 60(6), 305 (2015)
Pereira, R., et al.: Mutation analysis in patients with total sperm immotility. J. Assist. Reprod. Genet. 32(6), 893–902 (2015)
Antonarakis, S.E., Krawczak, M., Cooper, D.N.: Disease-causing mutations in the human genome. Eur. J. Pediatr. 159(Suppl), S173–S178 (2000)
Gripp, K.W., et al.: Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome. Am. J. Med. Genet. Part A 167(2), 271–281 (2015)
Norton, N., et al.: Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy. Am. J. Hum. Genet. 88(3), 273–282 (2011)
Sirmaci, A., et al.: Challenges in whole exome sequencing: an example from hereditary deafness. PLoS ONE 7(2), e32000 (2012)
Sauna, Z.E., Kimchi-Sarfaty, C.: Understanding the contribution of synonymous mutations to human disease. Nat. Rev. Genet. 12(10), 683–691 (2011)
Meienberg, J., et al.: Clinical sequencing: is WGS the better WES? Hum. Genet. 135(3), 359–362 (2016)
Belkadi, A., et al.: Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants. Hum. Genet. 135, 359–362 (2016)
Xu, W., et al.: Model-free linkage analysis of a binary trait. Stat. Hum. Genet.: Methods Protoc. 850, 317–345 (2012)
Bailey-Wilson, J.E.: Parametric and nonparametric linkage analysis. In: Encyclopedia of Life Sciences. Wiley, Chichester (2006)
Pulst, S.M., et al.: Genetic linkage analysis. Arch. Neurol. 56(6), 667 (1999)
Ott, J.: Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies. Am. J. Hum. Genet. 26(5), 588 (1974)
Elston, R.C., Stewart, J.: A general model for the genetic analysis of pedigree data. Hum. Hereditary 21, 523–542 (1971)
Kruglyak, L., et al.: Parametric and nonparametric linkage analysis: a unified multipoint approach. Am. J. Hum. Genet. 58, 1347–1363 (1996)
Ghahramani, Z.: An introduction to hidden Markov models and Bayesian networks. Int. J. Pattern Recogn. Artif. Intell. 15(1), 9–42 (2001)
Goedken, R., et al.: Drawbacks of GENEHUNTER for larger pedigrees: application to panic disorder. Am. J. Med. Genet. 96(6), 781–783 (2000)
Sobel, E., Lange, K.: Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am. J. Hum. Genet. 58(6), 1323–1337 (1996)
Geyer, C.: Introduction to Markov chain Monte Carlo. In: Brooks, S., et al. (eds.) Handbook of Markov Chain Monte Carlo, pp. 3–48. CRC Press, Boca Raton (2011)
Romero-Hidalgo, S., et al.: GENEHUNTER versus SimWalk2 in the context of an extended kindred and a qualitative trait locus. Genetica 123(3), 235–244 (2005)
Abecasis, G.R., et al.: Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30(1), 97–101 (2002)
Dudbridge, F.: A survey of current software for linkage analysis. Hum. Genomics 1(1), 63 (2003)
MacCluer, J.W., et al.: Pedigree analysis by computer simulation. Zoo Biol. 5(2), 147–160 (1986)
Gudbjartsson, D.F., et al.: Allegro, a new computer program for multipoint linkage analysis. Nat. Genet. 25(1), 12–13 (2000)
Alkuraya, F.S.: The application of next-generation sequencing in the autozygosity mapping of human recessive diseases. Hum. Genet. 132(11), 1197–1211 (2013)
Krawitz, P.M., et al.: Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome. Nat. Genet. 42(10), 827–829 (2010)
Becker, J., et al.: Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. Am. J. Hum. Genet. 88(3), 362–371 (2011)
Seelow, D., Schuelke, M.: HomozygosityMapper2012—bridging the gap between homozygosity mapping and deep sequencing. Nucleic Acids Res. 40(W1), W516–W520 (2012)
Seelow, D., et al.: HomozygosityMapper—an interactive approach to homozygosity mapping. Nucleic Acids Res. 37(Web Server issue), W593–W599 (2009)
Purcell, S., et al.: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81(3), 559–575 (2007)
Gusev, A., et al.: Whole population, genome-wide mapping of hidden relatedness. Genome Res. 19(2), 318–326 (2009)
Görmez, Z., et al.: HomSI: a homozygous stretch identifier from next-generation sequencing data. Bioinformatics 30(3), 445–447 (2013)
Magi, A., et al.: H3M2: detection of runs of homozygosity from whole-exome sequencing data. Bioinformatics 30(20), 2852–2859 (2014)
Carr, I.M., et al.: Autozygosity mapping with exome sequence data. Hum. Mutat. 34(1), 50–56 (2013)
Seelow, D., et al.: GeneDistiller—distilling candidate genes from linkage intervals. PLoS ONE 3(12), e3874 (2008)
Pippucci, T., et al.: EX-HOM (EXome HOMozygosity): a proof of principle. Hum. Hered. 72(1), 45–53 (2011)
Tang, R., et al.: A variable-sized sliding-window approach for genetic association studies via principal component analysis. Ann. Hum. Genet. 73(Pt 6), 631–637 (2009)
Barrett, J.C., et al.: Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2), 263–265 (2004)
Chang, C.: PLINK: whole genome data analysis toolset-identity by descent. https://www.cog-genomics.org/plink/1.9/ibd#homozyg
Pippucci, T., et al.: Detection of runs of homozygosity from whole exome sequencing data: state of the art and perspectives for clinical, population and epidemiological studies. Hum. Hered. 77(1–4), 63–72 (2014)
Oliveira, J., et al.: Homozygosity mapping using whole-exome sequencing: a valuable approach for pathogenic variant identification in genetic diseases. In: Proceedings of the 10th International Joint Conference on Biomedical Engineering Systems and Technologies, BIOINFORMATICS, (BIOSTEC 2017), vol. 3, pp. 210–216 (2017)
Leigh, M.W., et al.: Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome. Genet. Med.: Off. J. Am. Coll. Med. Genet. 11(7), 473–487 (2009)
Acknowledgements
The authors acknowledge support from: (i) Fundação para a Ciência e Tecnologia (FCT) [Grant ref.: PD/BD/105767/2014] (R.P.); (ii) Research grant attributed by “Fundo para a Investigação e Desenvolvimento do Centro Hospitalar do Porto” [Grant ref.: 336-13(196-DEFI/285-CES)] (J.O.). The work was also supported by the Institutions of the authors and in part by UMIB, which is funded by through FCT under the Pest-OE/SAU/UI0215/2014. The authors would like to thank the clinicians for patient referral.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG, part of Springer Nature
About this paper
Cite this paper
Oliveira, J., Pereira, R., Santos, R., Sousa, M. (2018). Evaluating Runs of Homozygosity in Exome Sequencing Data - Utility in Disease Inheritance Model Selection and Variant Filtering. In: Peixoto, N., Silveira, M., Ali, H., Maciel, C., van den Broek, E. (eds) Biomedical Engineering Systems and Technologies. BIOSTEC 2017. Communications in Computer and Information Science, vol 881. Springer, Cham. https://doi.org/10.1007/978-3-319-94806-5_15
Download citation
DOI: https://doi.org/10.1007/978-3-319-94806-5_15
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-94805-8
Online ISBN: 978-3-319-94806-5
eBook Packages: Computer ScienceComputer Science (R0)