Overview of genetic variation
- Benjamin A Raby, MD, MPH
Benjamin A Raby, MD, MPH
- Section Editor — Genetics
- Associate Professor of Medicine
- Harvard Medical School
The human genome is rich in variation. Until recently, only a handful of common variants, termed polymorphisms (chromosome or sequence variants found in more than 1 percent of the population), have been implicated in common disease, although the majority of heritable phenotypic variation is due to alterations in DNA sequence. In contrast, the genetics of Mendelian conditions caused by rare mutations that occur sporadically or that are inherited have been better characterized.
The Human Genome Project, completed in 2003, elucidated the complete sequence of the human reference genome . This sequence, together with the availability of DNA genotyping and sequencing methods capable of surveying variation in large numbers of individuals on a genome-wide scale, has led to rapid expansion of the list of common genetic variants that contribute to disease susceptibility, disease progression, and variability in treatment response.
This topic will review the types of genetic variation implicated in health and disease, with a particular focus on common genetic variants, including short tandem repeats (STRs), single nucleotide polymorphisms (SNPs), and copy number variants (CNVs).
A glossary of genetic terms is available separately. (See "Glossary of genetic terms".)
RARE CHROMOSOMAL ABERRATIONS
Chromosomal abnormalities that are visible using light microscopy can be classified into those due to aberrant chromosome number and those due to abnormal chromosome structure. These variants can result in well-characterized syndromes, although many structural abnormalities are rare or unique. Chromosome aberrations typically result from either chromosome recombination errors during meiosis (for germline mutations) or aberrant chromosomal segregation during meiosis or mitosis. Large-scale variants can be evaluated using a variety of cytogenetic approaches, including karyotyping, fluorescence in-situ hybridization (FISH), and array comparative genome hybridization (array CGH) applications. (See 'Aneuploidy' below and 'Structural chromosome abnormalities' below and "Tools for genetics and genomics: Cytogenetics and molecular genetics".)
- Collins FS, Green ED, Guttmacher AE, et al. A vision for the future of genomics research. Nature 2003; 422:835.
- Ranweiler R. Assessment and care of the newborn with Down syndrome. Adv Neonatal Care 2009; 9:17.
- Kesler SR. Turner syndrome. Child Adolesc Psychiatr Clin N Am 2007; 16:709.
- Hjerrild BE, Mortensen KH, Gravholt CH. Turner syndrome and clinical treatment. Br Med Bull 2008; 86:77.
- Wikström AM, Dunkel L. Klinefelter syndrome. Best Pract Res Clin Endocrinol Metab 2011; 25:239.
- Otter M, Schrander-Stumpel CT, Curfs LM. Triple X syndrome: a review of the literature. Eur J Hum Genet 2010; 18:265.
- Higuchi M, Kazazian HH Jr, Kasch L, et al. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proc Natl Acad Sci U S A 1991; 88:7405.
- Hu XY, Ray PN, Worton RG. Mechanisms of tandem duplication in the Duchenne muscular dystrophy gene include both homologous and nonhomologous intrachromosomal recombination. EMBO J 1991; 10:2471.
- Lau YL, Srivastava G, Wong V, et al. Deletions, duplications and novel restriction fragment length polymorphism in Duchenne and Becker muscular dystrophies. Clin Genet 1992; 41:252.
- Cohn DH, Zhang X, Byers PH. Homology-mediated recombination between type I collagen gene exons results in an internal tandem duplication and lethal osteogenesis imperfecta. Hum Mutat 1993; 2:21.
- Jennings MW, Jones RW, Wood WG, Weatherall DJ. Analysis of an inversion within the human beta globin gene cluster. Nucleic Acids Res 1985; 13:2897.
- Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003; 348:1201.
- Van den Berghe H. Letter: The Ph1-chromosome: translocation to chromosome 9. Lancet 1973; 302:1030.
- Lupski JR, Reid JG, Gonzaga-Jauregui C, et al. Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med 2010; 362:1181.
- 1000 Genomes Project Consortium, Abecasis GR, Altshuler D, et al. A map of human genome variation from population-scale sequencing. Nature 2010; 467:1061.
- Chakravarti A. It's raining SNPs, hallelujah? Nat Genet 1998; 19:216.
- Li WH, Sadler LA. Low nucleotide diversity in man. Genetics 1991; 129:513.
- Stephens JC, Schneider JA, Tanguay DA, et al. Haplotype variation and linkage disequilibrium in 313 human genes. Science 2001; 293:489.
- Halushka MK, Fan JB, Bentley K, et al. Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat Genet 1999; 22:239.
- Rideout WM 3rd, Coetzee GA, Olumi AF, Jones PA. 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science 1990; 249:1288.
- Cooper DN, Krawczak M. Human Gene Mutation Database. Hum Genet 1996; 98:629.
- Prins BP, Lagou V, Asselbergs FW, et al. Genetics of coronary artery disease: genome-wide association studies and beyond. Atherosclerosis 2012; 225:1.
- Guerra SG, Vyse TJ, Cunninghame Graham DS. The genetics of lupus: a functional perspective. Arthritis Res Ther 2012; 14:211.
- Marian AJ. Elements of 'missing heritability'. Curr Opin Cardiol 2012; 27:197.
- Krawczak M, Cooper DN. Gene deletions causing human genetic disease: mechanisms of mutagenesis and the role of the local DNA sequence environment. Hum Genet 1991; 86:425.
- Taylor MS, Ponting CP, Copley RR. Occurrence and consequences of coding sequence insertions and deletions in Mammalian genomes. Genome Res 2004; 14:555.
- Antonarakis SE, Krawczak M, Cooper DN. Disease-causing mutations in the human genome. Eur J Pediatr 2000; 159 Suppl 3:S173.
- Kerem B, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989; 245:1073.
- Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245:1066.
- Rommens JM, Zengerling S, Burns J, et al. Identification and regional localization of DNA markers on chromosome 7 for the cloning of the cystic fibrosis gene. Am J Hum Genet 1988; 43:645.
- Liu R, Paxton WA, Choe S, et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 1996; 86:367.
- Samson M, Libert F, Doranz BJ, et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 1996; 382:722.
- Eugen-Olsen J, Iversen AK, Garred P, et al. Heterozygosity for a deletion in the CKR-5 gene leads to prolonged AIDS-free survival and slower CD4 T-cell decline in a cohort of HIV-seropositive individuals. AIDS 1997; 11:305.
- Schlötterer C. Evolutionary dynamics of microsatellite DNA. Chromosoma 2000; 109:365.
- Ellegren H. Microsatellite mutations in the germline: implications for evolutionary inference. Trends Genet 2000; 16:551.
- A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell 1993; 72:971.
- Lalioti MD, Scott HS, Buresi C, et al. Dodecamer repeat expansion in cystatin B gene in progressive myoclonus epilepsy. Nature 1997; 386:847.
- Muragaki Y, Mundlos S, Upton J, Olsen BR. Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13. Science 1996; 272:548.
- Verkerk AJ, Pieretti M, Sutcliffe JS, et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 1991; 65:905.
- Buxton J, Shelbourne P, Davies J, et al. Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy. Nature 1992; 355:547.
- Harley HG, Brook JD, Rundle SA, et al. Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy. Nature 1992; 355:545.
- Iannuzzi MC, Collins FS. Reverse genetics and cystic fibrosis. Am J Respir Cell Mol Biol 1990; 2:309.
- Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17:405.
- RARE CHROMOSOMAL ABERRATIONS
- Numerical chromosome abnormalities
- - Aneuploidy
- - Polyploidy
- Structural chromosome abnormalities
- COMMON GENETIC VARIATION
- Single nucleotide polymorphisms (SNPs)
- - Monogenic disease
- - Genetic basis of complex disease
- Insertion/deletion polymorphism
- Copy number variations (CNVs)
- Short tandem repeat markers
- - Microsatellite markers
- CLINICAL CLASSIFICATION OF DNA VARIANTS