Mendelian genetics and gene discovery

A pillar reading for students, researchers, and educators. The page traces the line from Mendel's 1866 segregation ratios in Pisum to the modern catalogue of more than ten thousand identified Mendelian phenotypes, organised around three subtopics: inheritance patterns, pedigree analysis with variable expression, and the mapping methods that turn a phenotype into a named gene. For research, education, and teaching; not a medical device, not for clinical use.

| 14 min read

Short version. Mendelian genetics is the framework in which a single-locus phenotype segregates in predictable ratios across generations. Gene discovery is the empirical programme that has, since the 1980s, mapped those phenotypes to specific positions in the genome and then to specific transcripts. The pedigree is the data structure that connects the two: it records what segregates, in whom, and across how many meioses, and it is the input to almost every formal mapping or risk-modelling computation. This pillar gathers three subtopics — inheritance patterns, pedigree analysis, mapping — and links each into the calculator and drawing pages on Evagene.

From peas to inborn errors

Gregor Mendel's 1866 paper in the Verhandlungen des naturforschenden Vereines in Brünn (Biodiversity Heritage Library facsimile) reported segregation ratios in Pisum sativum that today are summarised as the laws of segregation and independent assortment. The work was rediscovered in 1900 by de Vries, Correns, and Tschermak, after which the 3:1 monohybrid ratio and the 9:3:3:1 dihybrid ratio became the organising arithmetic of single-locus inheritance. The classic monohybrid arithmetic and the calculator that walks through it are at mendelian inheritance calculator.

The first application to humans was Archibald Garrod's 1902 description of alkaptonuria as an "inborn error of metabolism", published in the Lancet (PMID 12122881, reprint commentary; original Garrod 1902, Lancet 160:1616). Garrod observed sibship-recurrence and parental consanguinity in affected families, drew the parallel to Mendel's recessive ratios, and inferred a single recessive locus — a deduction made years before HGD (the gene encoding homogentisate 1,2-dioxygenase) was molecularly identified. Garrod's argument is the founding example of the inferential chain that this pillar covers: phenotype, family, segregation pattern, locus.

Thomas Hunt Morgan's Drosophila work (Morgan 1910, Science 32:120, on white-eye inheritance; JSTOR record) added sex linkage to the framework, mapped the white locus to the X chromosome, and gave classical genetics its first positional finding. Morgan and his students — Sturtevant, Bridges, Muller — turned recombination frequency into linear distance and made the chromosome a map. The X-linked patterns Morgan documented are summarised on x-linked recessive calculator and x-linked dominant pedigree.

Botstein, White, Skolnick, and Davis 1980 (American Journal of Human Genetics 32:314, PMID 6247908) is the methodological hinge for human genetics. Their proposal — using restriction-fragment-length polymorphisms (RFLPs) as a dense, neutral genome-wide marker set — converted Mendel's segregation arithmetic into a practical recipe for finding the chromosomal address of any phenotype that segregates in families. Within a decade, that recipe had located HD (Huntington), CFTR (cystic fibrosis), and the BRCA loci.

The three subtopics in this pillar

The pillar splits into three deeper readings, each of which can be read on its own and each of which links back to the relevant Evagene calculator or drawing page.

1. Inheritance patterns

Inheritance patterns covers the canonical Mendelian categories — autosomal dominant, autosomal recessive, X-linked recessive, X-linked dominant, Y-linked, mitochondrial — and the non-classical mechanisms that complicate them: imprinting, uniparental disomy, anticipation, and locus heterogeneity. The page walks through the diagnostic features of each category: vertical transmission and roughly fifty per cent recurrence in autosomal dominant; sibship recurrence and unaffected obligate-carrier parents in autosomal recessive; the absence of male-to-male transmission in X-linked recessive; the silent-parent characteristic of imprinting disorders.

Worked examples cite the canonical loci where the pattern was first or most clearly established — DMD for X-linked recessive (Hoffman et al. 1987), HBB for autosomal recessive (sickle-cell anaemia, Ingram 1957), FBN1 for autosomal dominant Marfan (Dietz et al. 1991), SNRPN/UBE3A at 15q11-13 for the Prader-Willi / Angelman pair as the textbook imprinting example. The page links each pattern to the corresponding Evagene calculator: autosomal dominant calculator, autosomal recessive calculator, x-linked recessive calculator, x-linked dominant pedigree, mitochondrial inheritance pedigree, imprinting and UPD pedigree.

2. Pedigree analysis and variable expression

Pedigree analysis and variable expression is the bridge between the textbook pattern and a real family. The categorical patterns above assume full penetrance, complete and uniform expressivity, no de novo events, and a clean phenotype definition. Real pedigrees rarely satisfy all four. The page covers reduced penetrance (Hereditary breast and ovarian cancer is the canonical illustration: not every BRCA1 carrier develops cancer, and not every cancer in a BRCA1 family is a BRCA1 cancer), variable expressivity (neurofibromatosis type 1, NF1, where members of the same family present with different combinations of neurofibromas, café-au-lait macules, optic glioma), age-dependent penetrance (Huntington disease and the BRCA-associated cancers), somatic and germline mosaicism (and the worked osteogenesis-imperfecta example covered separately on germline mosaicism calculator), pleiotropy, locus heterogeneity, allelic heterogeneity, and phenocopies.

The second half of the page covers Bayesian risk computation in pedigree analysis — the standard textbook example of estimating a woman's carrier probability for an X-linked recessive trait given that she has unaffected sons. The before-and-after probability table is the entry point into the carrier probability calculator and the wider mendelian inheritance calculator. The page also covers Hardy-Weinberg-derived priors and the role of population-specific allele frequencies. Standard pedigree notation, on which all of the above depends, is at NSGC pedigree notation and the practical tool at pedigree drawing tool.

3. Mapping and gene identification

Mapping and gene identification covers the empirical chain by which a phenotype with a Mendelian pattern is located in the genome and then resolved to a specific gene. Classical linkage analysis and the LOD score (Morton 1955), positional cloning (Huntington 1993, cystic fibrosis 1989), the move from linkage to association (Risch & Merikangas 1996), the GWAS era (Klein et al. 2005 on age-related macular degeneration, Wellcome Trust Case Control Consortium 2007), the use of exome sequencing for monogenic-disorder gene discovery (Ng et al. 2009, 2010), the role of whole-genome sequencing, the 100,000 Genomes Project (Caulfield et al. 2017), and Matchmaker Exchange (Philippakis et al. 2015) for ultra-rare phenotypes are all covered.

Why pedigrees are still the data structure

Genome-scale data has not displaced the pedigree; it has made the pedigree more important. Whole-exome and whole-genome sequencing produce variant lists that are vastly larger than the number of variants any single individual carries that are causal of a Mendelian phenotype, and the standard filtering recipes — segregation in the family, de novo status in a trio, phenotypic homogeneity across affected sibs — all require an accurate pedigree. The pedigree is also the input to family-history risk-model algorithms (BRCAPRO, MMRpro, PancPRO, the Tyrer / Duffy / Cuzick 2004 model implemented as the IBIS-style approximation in Evagene, BOADICEA via the CanRisk file bridge), to segregation analysis, and to recurrence-risk computation in genetic counselling teaching scenarios. Documentation conventions are covered at pedigree chart; the practical drawing tool is at pedigree drawing tool.

The Online Mendelian Inheritance in Man catalogue (omim.org), originally compiled by Victor McKusick from 1966, currently lists more than ten thousand Mendelian phenotypes for which a molecular basis has been identified. The Human Phenotype Ontology (hpo.jax.org) provides the controlled vocabulary that lets phenotype information cross between OMIM, GeneReviews, and the literature; Phenopackets pedigree covers the structured-data interchange. Variant-level interpretation is at ClinVar, gene-level reviews at GeneReviews.

A note on what this pillar does not cover

This pillar is about classical Mendelian genetics, pedigree analysis, and gene discovery. Three adjacent topics that intersect but are not the focus here: complex-trait genetics with empirical recurrence tables (the polygenic / oligogenic model used in complex disease pedigree software); somatic-genomic events that do not transmit through the germline (covered briefly under mosaicism on the analysis page); and the engineering side of variant interpretation under ACMG/AMP criteria, which is downstream of the gene-discovery work covered here.

Evagene is an academic, research, and educational pedigree modelling platform. It supports structured family-history documentation, teaching, and exploratory use of published risk models, and is not intended to diagnose, prevent, monitor, predict, treat, or manage disease, determine eligibility for screening, testing, referral, or treatment, or replace professional clinical judgement. Outputs are illustrative and for educational and research purposes only. The Tyrer-Cuzick implementation in Evagene is an IBIS-style approximation of the published Tyrer / Duffy / Cuzick 2004 algorithm and not the official IBIS Breast Cancer Risk Evaluator binary. BOADICEA is licensed by the University of Cambridge and is not bundled in Evagene; Evagene exports a CanRisk 2.0 pedigree file that is uploaded at canrisk.org.

Key references

  • Mendel G. 1866. Versuche über Pflanzen-Hybriden. Verhandlungen des naturforschenden Vereines in Brünn 4:3-47. Biodiversity Heritage Library.
  • Garrod AE. 1902. The incidence of alkaptonuria: a study in chemical individuality. Lancet 160:1616-1620. PubMed PMID 12122881.
  • Morgan TH. 1910. Sex limited inheritance in Drosophila. Science 32:120-122. JSTOR 1635471.
  • Botstein D, White RL, Skolnick M, Davis RW. 1980. Construction of a genetic linkage map in man using restriction fragment length polymorphisms. Am J Hum Genet 32:314-331. PMID 6247908.
  • OMIM — Online Mendelian Inheritance in Man. omim.org.
  • GeneReviews. NIH/NCBI Bookshelf. ncbi.nlm.nih.gov/books/NBK1116.
  • Human Phenotype Ontology. hpo.jax.org.
  • ClinVar. ncbi.nlm.nih.gov/clinvar.

Related Evagene pages

Try Evagene for teaching and research pedigree modelling

In-browser pedigree drawing with NSGC notation, gesture drawing, GEDCOM and CanRisk export, and a 1,900-entry help catalogue. Free during alpha for clinicians, researchers, educators, and students. Outputs are illustrative and for educational / research purposes only.

Join the Alpha Waiting List