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  • Review Article
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Human genetics and disease

Beyond Mendel: an evolving view of human genetic disease transmission

Nature Reviews Genetics volume 3, pages 779–789 (2002)Cite this article

Key Points

  • Traditionally, genetic disorders have been classified as monogenic (involving one gene) or complex (involving many genes and their interaction with each other and the environment).

  • The identification of numerous disease genes has revealed that the pattern of transmission of certain genetic diseases deviates from the monogenic model.

  • Oligogenic disorders manifest a spectrum of complexity ranging from the phenotypic modification of a single allele by an allele at another locus, to complex gene and protein relationships.

  • Traditional tools for investigating complex relationships between genes can be successful in establishing the oligogenic basis of a genetic disorder and for modelling oligogenic traits using Mendelian principles.

  • The establishment of oligogenic behaviour and the expansion of models to explain the inheritance of disease alleles can catalyse the discovery of new disease genes through functional approaches.

  • In the absence of functional assays or an animal model, oligogenic mutations are often subtle and more difficult to recognize.

  • The molecular basis of oligogenicity requires a direct or indirect interaction of mutated proteins. These interactions might be due to the presence of multi-protein complexes, pleiotropic signalling pathways, complementary pathways or overlapping networks of protein function.

Abstract

Methodological and conceptual advances in human genetics have led to the identification of an impressive number of human disease genes. This wealth of information has also revealed that the traditional distinction between Mendelian and complex disorders might sometimes be blurred. Genetic and mutational data on an increasing number of disorders have illustrated how phenotypic effects can result from the combined action of alleles in many genes. In this review, we discuss how an improved understanding of the genetic basis of multilocus inheritance is catalysing the transition from a segmented view of human genetic disease to a conceptual continuum between Mendelian and complex traits.

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Figure 1: Complexity in monogenic diseases.
Figure 2: Idealized pedigrees showing examples of complex phenotypic modulation.
Figure 3: Triallelic inheritance.
Figure 4: Models of non-allelic complementation.
Figure 5: Idealized pathway-complementation schemes.

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Acknowledgements

We apologize to those researchers whose work we were unable to represent due to space constraints. We thank J. Groman and G. Cutting for sharing their unpublished data with us, and G. Cutting, S. Huston and J. Lupski for constructive discussions and critique of this manuscript. This work was supported by the National Eye Institute, the National Institutes of Health and by a grant from March of Dimes to N.K.

Author information

Authors and Affiliations

  1. Institute of Genetic Medicine, Johns Hopkins University, 2–127 Jefferson Street Building, Baltimore, 21287, Maryland, USA

    Jose L. Badano & Nicholas Katsanis

  2. Wilmer Eye Institute, 600 North Wolfe Street, Baltimore, 21287, Maryland, USA

    Nicholas Katsanis

Authors
  1. Jose L. Badano
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Corresponding author

Correspondence to Nicholas Katsanis.

Related links

Related links

DATABASES

LocusLink

ALG6

APC

Apc

BBS2

BBS6

CFTR

COL17A1

CNTF

CYP1B1

EDNRB

FAP

GDNF

HLA class II

JAG1

LAMB3

Map1a

MBL

Mom1

moth1

MTAP1

Muc1

NOS1

NOTCH2

NPHS1

NPHS2

PAH

PMM2

RDS

ROM1

SOD1

TGFB1

tub

OMIM

Bardet–Biedl syndrome

cystic fibrosis

familial amyotrophic lateral sclerosis

FAP

Finnish congenital nephrotic syndrome

generalized atrophic benign epidermolysis bullosa

Hirschsprung disease

hyperphenylalaninaemia

junctional epidermolysis bullosa

juvenile open-angle glaucoma

PKU

RP

schizophrenia

segmental glomerulosclerosis

WormBase

UNC-13

FURTHER INFORMATION

Nicholas Katsanis' lab

Glossary

PHENYLKETONURIA

An inborn error of metabolism that is caused by lack of the enzyme PAH that converts phenylalanine to tyrosine. If left untreated, it causes abnormally high phenylalanine levels and severe, progressive mental retardation, but can be prevented by neonatal screening and a low phenylalanine diet from an early age.

TETRAHYDROBIOPTERIN

Phenylalanine hydroxylase (PAH) is an oxygenase that couples an electron from a tetrahydrobiopterin cofactor (BH4) and an oxygen atom to hydroxylate phenylalanine to form tyrosine. Consequently, any defects in BH4 biosynthesis impair PAH function.

FAMILIAL ADENOMATOUS POLYPOSIS

(FAP). The development of numerous adomatous polyps in the colon that might progress to carcinomas.

QUANTITATIVE TRAIT LOCUS

(QTL). A genetic locus or chromosomal region that contributes to variability in complex quantitative traits (such as height or body weight), as identified by statistical analysis. Quantitative traits are typically affected by several genes and by the environment.

RETINITIS PIGMENTOSA

(RP). A group of both clinically and genetically heterogeneous hereditary retinal degeneration disorders that are caused by the death of both rod and cone photoreceptors, leading to a complete loss of vision.

BARDET–BIEDL SYNDROME

(BBS). A rare and genetically heterogeneous disorder that is characterized primarily by obesity, retinal dystrophy, polydactyly, hypogenitalism, learning difficulties and renal malformations.

HAPLOTYPE ANALYSIS

The study of the pattern of descent of a combination of alleles at different sites on a single chromosome (known as a haplotype). It is used for the identification of recombination events between markers and traits during linkage studies, thereby establishing the boundaries of the location of a phenotype-associated locus.

CONSANGUINEOUS

Descended from a recent common ancestor.

ENTERIC GANGLIA

Parasympathetic mass of nerve tissue (ganglia) in the colon.

PENETRANCE

The proportion of affected individuals among the carriers of a particular genotype. If all individuals who have a disease genotype show the disease phenotype, then the disease is said to be “completely penetrant”.

HERITABILITY

The proportion of the variation in a given characteristic or state that can be attributed to genetic factors.

PARAMETRIC LINKAGE

Parametric analyses are statistical tests for linkage that use assumptions such as mode of transmission, allele frequencies and penetrance.

NON-PARAMETRIC LINKAGE

Non-parametric approaches are statistical procedures that are not based on models, or assumptions pertaining to the distribution of the quantitative trait.

LOD SCORE

(Base 10 'logarithm of the odds' or 'log-odds'). A method of hypothesis testing. The logarithm of the ratio between likelihoods under the null and alternative hypotheses.

NEPHROTIC SYNDROME

Malfunction of the renal glomerular filtration barrier (a structure in the glomerulus that is responsible for protein filtration) that lead to the loss of plasma proteins.

GLAUCOMA

The abnormally elevated pressure in the liquid that fills the anterior part of the eye (the aqueous humour).

LINKAGE DISEQUILIBRIUM

The condition in which the frequency of a particular haplotype for two loci is significantly greater than that expected from the product of the observed allelic frequencies at each locus.

GENETIC DRIFT

Random fluctuations in the allele and, less commonly, the phenotype frequencies, as genes are transmitted from one generation to the next.

ALAGILLE SYNDROME

A dominantly inherited disorder that is characterized primarily by a scarcity of bile ducts in the liver. Other features include heart, eye, kidney and skeletal abnormalities, as well as defects in the central nervous system.

HAPLOINSUFFICIENCY

A gene dosage effect that occurs when a diploid requires both functional copies of a gene for a wild-type phenotype. An organism that is heterozygous for a haploinsufficient locus does not have a wild-type phenotype.

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Badano, J., Katsanis, N. Beyond Mendel: an evolving view of human genetic disease transmission. Nat Rev Genet 3, 779–789 (2002). https://doi.org/10.1038/nrg910

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