Mechanisms of tissue and cell-type specificity in heritable traits and diseases


Hundreds of heritable traits and diseases that are caused by germline aberrations in ubiquitously expressed genes manifest in a remarkably limited number of cell types and tissues across the body. Unravelling mechanisms that govern their tissue-specific manifestations is critical for our understanding of disease aetiologies and may direct efforts to develop treatments. Owing to recent advances in high-throughput technologies and open resources, data and tools are now available to approach this enigmatic phenomenon at large scales, both computationally and experimentally. Here, we discuss the large prevalence of tissue-selective traits and diseases, describe common molecular mechanisms underlying their tissue-selective manifestation and present computational strategies and publicly available resources for elucidating the molecular basis of their genotype–phenotype relationships.

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Fig. 1: The tissue selectivity of heritable diseases and traits and their associated genes.
Fig. 2: Illustration of the different mechanisms underlying tissue-selective manifestation of heritable traits and diseases.
Fig. 3: A schematic flow chart illuminating tissue-selectivity mechanisms.


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We thank A. Rudich, V. Chalifa-Caspi, A. Monsonego and members of the Yeger-Lotem lab for their helpful comments.

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Both authors contributed to all aspects of the article.

Correspondence to Esti Yeger-Lotem.

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Nature Reviews Genetics thanks M. Kuijjer and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

3D Genome:

Database of Small Human Non-coding RNAs (DASHR):


Disease Ontology:


Encyclopedia of DNA Elements (ENCODE):

Functional Annotation of the Mammalian Genome (FANTOM5):

Genetic Network Analysis Tool (GNAT):

Genotype-Tissue Expression (GTEx):


Human Cell Atlas:

Human Phenotype Ontology (HPO):

Human Protein Atlas (HPA):

Human Proteome Map:


US National Human Genome Research Institute–European Bioinformatics Institute (NHGRI–EBI) GWAS Catalogue:

Online Mendelian Inheritance in Man (OMIM):



Roadmap Epigenomics Project:

Single Cell portal:

SPECific Tissue/Tumour Related PPI networks Analyser (SPECTRA):



Tissue-specific Gene Expression and Regulation (TiGER):

Supplementary information


Heritable traits and diseases

Phenotypes with a heritable monogenic or polygenic component due to inherited or de novo germline aberrations present throughout the body.

Germline aberrations

Aberrations (inherited or de novo) that are common to all cells harbouring the individual’s genome.

Causal genes

Genes containing a variant that was found to lead to disease.

Pathogenic tissues

The tissues that elicit the disease.

Complex traits

Traits caused by variations in multiple genes or non-coding genomic regions potentially in combination with other factors such as environmental exposure or lifestyle.

Genome-wide association studies

(GWAS). Studies that scan genetic variants across individuals to identify variants that are significantly associated with a trait (the variants are known as risk alleles when they are associated with disease occurrence).


A trait caused by variation in a single gene.

Susceptible tissue

The tissue that manifests a trait or disease.

Tissue-exclusive expression

When expression of a gene exceeds a predefined cut-off in a single tissue. This is in contrast to tissue-selective expression, which refers to expression in a subset of tissues (>1 tissue).

Preferential expression

When expression of a gene is elevated in a certain tissue relative to its expression in other tissues.


A homologous gene present in the same organism, typically having redundant functionality.

Expression quantitative trait loci

(eQTLs). Genomic regions containing DNA sequence variants that influence the mRNA expression level of a gene.

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Hekselman, I., Yeger-Lotem, E. Mechanisms of tissue and cell-type specificity in heritable traits and diseases. Nat Rev Genet 21, 137–150 (2020).

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