From genes to proteins

DNA and the genome

Each strand of DNA is a chain of four kinds of unit, named by their bases A, C, G and T; in a protein-coding gene, their order specifies the order of amino acids ¹².

Two antiparallel strands form a right-handed double helix; adenine pairs with thymine and guanine with cytosine, so each strand’s sequence fixes the other’s ¹³. Of over 44,400 human genes named by the HUGO Gene Nomenclature Committee, over 19,250 encode proteins ⁴.

From gene to protein

A cell copies a gene into RNA, cuts out stretches called introns, and reads the rest three bases at a time to join amino acids ⁶⁷².

RNA polymerase II extends precursor mRNA at its 3′ end, complementary to the template strand ⁶. RNGTT adds GMP from GTP to the 5′ end, and RNMT methylates this guanosine at N7 with S-adenosylmethionine ⁶. The spliceosome excises introns; of 22,489 EST-supported mammalian splice-site pairs, 98.71% were GT–AG ⁷. Poly(A) polymerase adds the 3′ tail ⁶.

The 43S pre-initiation complex scans from the cap to the AUG start codon ⁶. Of 64 codons, 61 specify the 20 standard amino acids and three stop translation ². eEF1A·GTP delivers aminoacyl-tRNAs, the ribosome forms each peptide bond and eEF2·GTP drives translocation ⁶.

From gene to proteinNucleus for transcription and mRNA processing; cytosol for translation

Gene (template DNA strand)
RNA polymerase II (catalytic subunit POLR2A)ATP, CTP, GTP and UTP, Mg2+ (two ions)Adds one nucleotide at a time to the 3′ end, complementary to the template
Pre-mRNA
mRNA-capping enzyme (RNGTT), then cap methyltransferase (RNMT)GTP, S-adenosylmethionineDuring transcription; forms the 7-methylguanosine cap at the 5′ end
Capped pre-mRNA
Spliceosome (U1, U2, U4/U6 and U5 snRNPs); poly(A) polymerase (PAPOLA)ATP for the poly(A) tailIntrons excised; 98.71% of 22,489 mammalian splice-site pairs are GT–AG
Mature mRNA
Ribosome, with elongation factors eEF1A and eEF2Aminoacyl-tRNAs, GTPCodons read from the AUG start codon to one of three stop codons
Polypeptide

Variants and single-gene traits

A variant is a difference in DNA sequence between people, from one base to whole exons ⁸.

About 85% of pathogenic LDLR variants are missense, nonsense, splice-site or small insertion–deletion variants detectable by sequencing; about 15% are larger intragenic deletions or duplications ⁸.

Variant	One copy	Two copies
PAH, pathogenic	Asymptomatic carrier ⁹	Phenylalanine hydroxylase deficiency ⁹
HBB c.20A>T	Sickle cell trait, without anaemia ¹⁰	Sickle cell disease ¹⁰
LDLR, pathogenic	Half the functional LDL receptors; LDL about doubled ¹¹	Untreated adult LDL cholesterol often above 13 mmol/L ⁸
ALDH22*, rs671	No detectable liver ALDH2 activity, 13 of 13 ¹²	No detectable activity, 1 of 1 ¹²
LCT −13910C>T	Lactase persistence ¹³	Lactase persistence ¹³

HBB c.20A>T replaces glutamate 6 of mature β-globin with valine, p.Glu7Val in HGVS numbering ¹⁰. In deoxygenated haemoglobin S, valine 6 binds complementary regions of adjacent molecules, forming insoluble polymers that distort red cells; carriers have a survival advantage in childhood malaria ¹⁰.

One ALDH2*2 subunit, with lysine for glutamate 504 of the precursor, renders the tetramer nearly inactive ¹⁴; about 36% of East Asians flush after alcohol ¹⁵.

Oxidation of ethanolHepatocyte cytosol and mitochondria, then extrahepatic tissues

Ethanol
Class I alcohol dehydrogenases (ADH1A, ADH1B, ADH1C), cytosolicNAD+ to NADHCYP2E1 (NADPH, O2) and catalase (CAT, H2O2) also form acetaldehyde
Acetaldehyde
Aldehyde dehydrogenase 2 (ALDH2), mitochondrialNAD+ to NADHDisulfiramA single ALDH2*2 (rs671) subunit renders the tetramer nearly inactive
Acetate
Acetyl-CoA synthetases ACSS2 (cytosol) and ACSS1 (mitochondria)ATP to AMP and pyrophosphate, CoAThe liver releases acetate into blood; extrahepatic tissues oxidise it
Acetyl-CoA

LCT −13910C>T (rs4988235) is one of at least five independent lactase-persistence variants in an LCT enhancer within intron 13 of MCM6 ¹³¹⁶.

Polygenic traits

Inherited differences in height, as in many traits, are spread across very many variants with tiny effects ¹⁷.

Genome-wide, the median SNP was associated with 0.14 mm of height, a tenth of the 1.43 mm median for genome-wide significant SNPs ¹⁷.

Mitochondrial DNA

Mitochondria have DNA of their own, and its variants pass to children only from the mother ¹⁸.

It encodes 13 respiratory-chain subunits, 2 ribosomal RNAs and 22 transfer RNAs ¹⁸. Cells hold thousands of copies; where mutant and normal copies coexist, a respiratory-chain defect appears only above a threshold mutant proportion ¹⁸.

Epigenetic marks

Cells with identical DNA keep different genes on or off through divisions, partly through chemical marks on DNA and histones ¹⁹.

DNMT1 methylates CpG cytosines, preferring hemimethylated DNA, and at replication sites maintains the methylation pattern on the new strand ⁶.

References

Independent research
Watson JD, Crick FHC. Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid Nature, 1953.
doi:10.1038/171737a0 PubMed 13054692
Funding and finding
Funding
One of us (J. D. W.) has been aided by a fellowship from the National Foundation for Infantile Paralysis.
Finding
Proposed structure: two right-handed helical chains of phosphate diester groups joining beta-D-deoxyribofuranose residues with 3',5' linkages, coiled round the same axis; the atoms of the two chains run in opposite directions; bases are on the inside and phosphates on the outside; adenine pairs with thymine and guanine with cytosine by hydrogen bonds, so the sequence of one chain determines the sequence of the other. The authors state that the structure must be regarded as unproved until checked against more exact results.
Independent research
Koonin EV, Novozhilov AS. Origin and evolution of the genetic code: the universal enigma IUBMB Life, 2009.
doi:10.1002/iub.146 PubMed 19117371
Funding and finding
Funding
The authors' research is supported by the Department of Health and Human Services intramural program (NIH, National Library of Medicine).
Finding
Review. The standard genetic code maps 64 codons, each a triplet of nucleotides, to 20 amino acids and two punctuation marks, start and stop signals; 61 codons code for amino acids and three are stop codons; the code is shared, with relatively minor modifications, by all known life forms. Selenocysteine and pyrrolysine are encoded by special schemes in subsets of organisms.
Independent research
Drew HR, Wing RM, Takano T, Broka C, Tanaka S, Itakura K, et al. Structure of a B-DNA dodecamer: conformation and dynamics Proceedings of the National Academy of Sciences of the United States of America, 1981.
doi:10.1073/pnas.78.4.2179 PubMed 6941276
Funding and finding
Funding
This work was carried out with the support of National Institutes of Health Grants GM-12121 and GM-24393 and National Science Foundation Grant PCM79-13959. H.R.D. was the recipient of a National Institutes of Health Predoctoral Traineeship.
Finding
The crystal structure of the synthetic dodecamer, refined to a residual error of 17.8% at 1.9 A resolution, is a right-handed Watson-Crick B double helix with an average of 10.1 base pairs per turn over the entire helix; coordinates were deposited with the Brookhaven Protein Data Bank.
Textbook or database
Seal RL, Braschi B, Gray K, McClay J, Tweedie S, Bruford EA. Genenames.org: the HGNC and PGNC resources in 2026 Nucleic Acids Research, 2026.
doi:10.1093/nar/gkaf1229 PubMed 41287213
Funding and finding
Funding
National Human Genome Research Institute of the National Institutes of Health [U24HG003345], the U.S. Department of Energy [DE-AC05-00OR22725], and SciBite (Elsevier). SciBite suggested additional gene groups, initially for drug-target genes, and funds their addition.
Finding
The HGNC, based at the University of Cambridge, approves unique symbols and descriptive names for human genes; the database contains over 44,400 approved symbols, over 19,250 of them for protein-coding genes. When a symbol changes, the HGNC ID stays the same.
Industry-funded
Nurk S, Koren S, Rhie A, Rautiainen M, Bzikadze AV, Mikheenko A, et al. The complete sequence of a human genome Science, 2022.
doi:10.1126/science.abj6987 PubMed 35357919
Funding and finding
Funding
Intramural Research Programs of the National Human Genome Research Institute and the National Library of Medicine, NIH; numerous NIH and NSF grants; Intramural funding at the National Institute of Standards and Technology; Wellcome (WT206194, WT207492); HHMI; Mark Foundation for Cancer Research; Chan Zuckerberg Biohub Investigator Award; Max Planck Society; St. Petersburg State University; Ministry of Science and Higher Education of the Russian Federation; Swiss National Science Foundation; ERC; German Federal Ministry for Research and Education; Connecticut Innovations; and personal fellowships, as listed in the paper.
In-kind support
Computational support from AnVIL, Amazon Web Services, DNAnexus, the UW Genome Sciences IT Group and the UConn Computational Biology Core.
Finding
T2T-CHM13 includes gapless telomere-to-telomere assemblies of all 22 autosomes and chromosome X, comprising 3,054,815,472 bp of nuclear DNA, plus a 16,569 bp mitochondrial genome; it covers the 8% of the genome missing from the earlier reference. Gene annotation: 19,969 protein-coding genes in T2T-CHM13 against 19,890 in GENCODE for GRCh38.
Textbook or database
UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.
doi:10.1093/nar/gkae1010 PubMed 39552041
Funding and finding
Funding
National Human Genome Research Institute (NHGRI) [HG002273]; Office of the Director, NIH OD [U24HG007822]; National Institute of Allergy and Infectious Diseases (NIAID); National Institute on Aging (NIA); National Institute of General Medical Sciences (NIGMS) [R35GM141873]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Eye Institute (NEI); National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); Biotechnology and Biological Sciences Research Council (BBSRC) [BB/T015608/1]; National Science Foundation's Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 - Research and Innovation Framework Programme [825575]; State Secretariat for Education, Research and Innovation (SERI); European Molecular Biology Laboratory (EMBL) Australia. Funding for open access charge: National Institutes of Health.
Finding
Reviewed human UniProtKB entries, release 2026_03, read through rest.uniprot.org on 2026-10-21. POLR2A (P24928): catalytic core component of RNA polymerase II, which synthesises mRNA precursors from the four ribonucleoside triphosphates, appends one nucleotide at a time to the 3' end of the nascent RNA on the basis of complementarity with the template DNA strand, uses two Mg2+ ions, and cooperates in co-transcriptional 5'-end capping and co-transcriptional splicing. RNGTT (O60942): removes the gamma-phosphate from the 5'-triphosphate end of nascent mRNA and transfers the GMP moiety of GTP to the 5'-diphosphate end. RNMT (O43148): methylates the N7 position of the added guanosine of the 5' cap with S-adenosyl-L-methionine. PAPOLA (P51003): creates the 3' poly(A) tail of mRNAs from ATP. EIF1 (P41567): component of the 43S pre-initiation complex, which binds the cap-proximal region, scans the 5' untranslated region and locates the initiation codon; essential for start-codon recognition on the basis of AUG nucleotide context and location relative to the cap. EEF1A1 (P68104): catalyses the GTP-dependent binding of aminoacyl-tRNA to the ribosomal A site; codon-anticodon base pairing promotes GTP hydrolysis; the ribosome then forms the peptide bond. EEF2 (P13639): catalyses the GTP-dependent ribosomal translocation step. DNMT1 (P26358): methylates CpG residues, preferentially hemimethylated DNA, and associates with replication sites in S phase, maintaining the methylation pattern on the newly synthesised strand.
Independent research
Burset M, Seledtsov IA, Solovyev VV. Analysis of canonical and non-canonical splice sites in mammalian genomes Nucleic Acids Research, 2000.
doi:10.1093/nar/28.21.4364 PubMed 11058137
Funding and finding
Funding
This work was supported by the Wellcome Trust grant to V.S. and grant FPI95 from Ministerio de Educación y Ciencia to M.B.
Finding
Of 22,489 EST-supported mammalian splice-site pairs, 98.71% had the canonical dinucleotides GT at the donor and AG at the acceptor site and 0.56% were GC-AG; after correction with human genomic sequence the authors estimate 99.24% GT-AG, 0.69% GC-AG, 0.05% AT-AC and 0.02% other pairs. Introns flanked by GT-AG are excised from pre-mRNA by the spliceosome containing the U1, U2, U4/U6 and U5 snRNPs; AT-AC introns by a spliceosome of U11, U12, U4atac/U6atac and U5 snRNPs.
Textbook or database
Ison HE, Clarke SL, Knowles JW. Familial Hypercholesterolemia GeneReviews, University of Washington, Seattle, 2025.
PubMed 24404629
Funding and finding
Funding
No funding statement in the chapter. Acknowledgments: The FH Foundation, AHA, NIH, Doris Duke Foundation.
Finding
Expert-authored, peer-reviewed chapter, first posted 2 January 2014, comprehensive update 7 July 2022, revised 30 January 2025. APOB-, LDLR- and PCSK9-related familial hypercholesterolaemia is inherited in an autosomal dominant manner. Pathogenic LDLR variants account for more than 50% of FH; of pathogenic LDLR variants, about 85% are identified by sequence analysis, which detects missense, nonsense and splice-site variants and small intragenic deletions/insertions, and about 15% by gene-targeted deletion/duplication analysis, which detects intragenic deletions or duplications. Heterozygous LDLR-related FH: LDL cholesterol often above 190 mg/dL. Biallelic LDLR pathogenic variants: untreated adults often have LDL cholesterol above 500 mg/dL (above 13 mmol/L), and most develop severe coronary artery disease by their mid-20s.
Textbook or database
Arnold G, Vockley J. Phenylalanine Hydroxylase Deficiency GeneReviews, University of Washington, Seattle, 2025.
PubMed 20301677
Funding and finding
Funding
not stated in the chapter
Finding
Expert-authored, peer-reviewed chapter, first posted 2000, comprehensive update 13 March 2025, revised 20 November 2025. Autosomal recessive; biallelic PAH variants; PAH at 12q23.2. Phenylketonuria denotes untreated plasma phenylalanine above 1,000 umol/L; untreated or late-diagnosed disease causes irreversible intellectual disability, seizures and microcephaly. Defects of tetrahydrobiopterin synthesis or recycling (GCH1, PTS, QDPR, PCBD1) account for about 2% of raised blood phenylalanine. Newborn screening uses dried blood spots collected 24 to 72 hours after birth, with phenylalanine and tyrosine measured by tandem mass spectrometry; biochemical diagnosis requires blood phenylalanine above 120 umol/L and a phenylalanine-to-tyrosine ratio of 3 or more. Treatment: phenylalanine-restricted diet with phenylalanine-free protein supplements based on amino acids or glycomacropeptide; 25% to 50% respond to sapropterin, a synthetic form of tetrahydrobiopterin; pegvaliase, a PEGylated phenylalanine ammonia lyase given subcutaneously, is approved in the US for adults with phenylalanine above 600 umol/L. Aspartame is metabolised in the gut to phenylalanine and aspartate. Maternal phenylalanine consistently above 360 umol/L in pregnancy causes intellectual disability in more than 90% of offspring. The chapter attributes brain toxicity to phenylacetic, phenylpyruvic and phenyllactic acids and to tyrosine and neurotransmitter deficiency.
Textbook or database
Bender MA, Carlberg K. Sickle Cell Disease GeneReviews, University of Washington, Seattle, 2025.
PubMed 20301551
Funding and finding
Funding
not stated in the chapter
Finding
Expert-authored, peer-reviewed chapter, first posted 15 September 2003, comprehensive update 17 November 2022, revised 13 February 2025. Sickle haemoglobin (HbS) results from HBB c.20A>T, p.Glu6Val in the hemoglobin convention that starts numbering after the initiator methionine (p.Glu7Val in standard HGVS numbering). Sickle cell disease is inherited in an autosomal recessive manner; Hb S/S is the most common form. In deoxygenated HbS, an interaction between Val6 and complementary regions on adjacent molecules forms highly ordered, insoluble polymers that distort red blood cells; HbS polymerises in the T conformation associated with deoxygenation but not in the R conformation. Heterozygotes (Hb A/S, sickle cell trait) are not anaemic, have normal red cell indices and HbS near 40%, and Hb A/S confers a survival advantage in children who contract malaria.
Independent research
Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins Cell, 2015.
doi:10.1016/j.cell.2015.01.036 PubMed 25815993
Funding and finding
Funding
The authors' experimental work over 40 years was supported by grants from the NIH (HL-20948), the Perot Foundation, the Moss Heart Foundation and the O'Donnell Foundation.
Finding
Narrative review. Cholesterol is a 27-carbon, four-ring molecule synthesised from acetate, a two-carbon unit attached to CoA; HMG-CoA reductase catalyses the rate-controlling step. An LDL particle contains about 1500 cholesteryl ester molecules in its core and a coat of about 800 phospholipid molecules, about 500 unesterified cholesterol molecules and one 500-kDa apoB. LDL receptors cluster in coated pits; internalised LDL reaches lysosomes, where cholesteryl esters are hydrolysed. The LDLR gene on the short arm of chromosome 19 has 18 exons and encodes a mature protein of 839 amino acids with seven cysteine-rich LDL-binding repeats and a 50-amino-acid cytoplasmic tail that directs it to coated pits. FH heterozygotes have half the functional receptors and about twofold LDL. Nuclear SREBP-2 activates the LDL receptor gene and the cholesterol biosynthetic genes; statins lower ER cholesterol, activate SREBP-2, raise hepatic LDL receptors and lower plasma LDL. Most LDL is removed by hepatic LDL receptors. PCSK9 binds hepatic LDL receptors and disrupts their recycling. African-Americans heterozygous for PCSK9 nonsense mutations Y142X or C679X had 28% lower LDL and 88% fewer heart attacks. Conclusions on human liver are extrapolated from rats, mice, hamsters and dogs.
Independent research
Crabb DW, Edenberg HJ, Bosron WF, Li TK. Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2(2) allele is dominant Journal of Clinical Investigation, 1989.
doi:10.1172/JCI113875 PubMed 2562960
Funding and finding
Participants
24
Funding
This work was carried out with support from the Indiana University Alcohol Research Center (P50 AA-07611) and grants to Dr. Crabb (AA-00081 and AA-06434) and Dr. Edenberg (AA-06460) from the National Institute on Alcohol Abuse and Alcoholism.
Finding
Of 24 Japanese livers, all 10 with active ALDH2 were ALDH2*1/*1; of the 14 without ALDH2 activity, 13 were heterozygous for ALDH2*2 and 1 homozygous, so the allele is dominant. ALDH2 is a homotetramer with a Km for acetaldehyde of about 1 µM; random association of equally expressed subunits would leave 6% fully normal tetramers in heterozygotes.
Independent research
Tishkoff SA, Reed FA, Ranciaro A, Voight BF, Babbitt CC, Silverman JS, et al. Convergent adaptation of human lactase persistence in Africa and Europe Nature Genetics, 2007.
doi:10.1038/ng1946 PubMed 17159977
Funding and finding
Participants
470
Funding
L.S.B. Leakey and Wenner Gren Foundation grants; US National Science Foundation grants BSC-0196183, BSC-0552486 and IGERT-9987590; US National Institutes of Health grants R01GM076637, F32HG03801 and HG002772-1; David and Lucile Packard and Burroughs Wellcome Foundation Career Awards; Duke University Institute for Genome Sciences and Policy; Wellcome Trust.
Finding
In most humans lactase-phlorizin hydrolase, which hydrolyses lactose into glucose and galactose in the small intestine, declines after weaning. Lactase persistence is inherited as a dominant trait in Europeans and its frequency exceeds 90% in Swedes and Danes, is about 50% in Spanish and French populations and about 1% in Chinese. C/T-13910 lies about 14 kb upstream of LCT within MCM6. Three African variants, G/C-14010, T/G-13915 and C/G-13907, arose on different haplotypes, are associated with lactase persistence and raise LCT promoter activity in vitro by about 18-30%; selection coefficients 0.04-0.097.
Independent research
Edenberg HJ, McClintick JN. Alcohol dehydrogenases, aldehyde dehydrogenases, and alcohol use disorders: a critical review Alcoholism: Clinical and Experimental Research, 2018.
doi:10.1111/acer.13904 PubMed 30320893
Funding and finding
Funding
Related work in the authors' laboratory is supported by NIH Grants U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and U01MH109532 from the National Institute on Mental Health (NIMH) and the National Institute on Drug Abuse (NIDA).
Finding
Class I ADH1A, ADH1B and ADH1C catalyse most hepatic ethanol oxidation; cytochrome P450s and catalase make only minor contributions. In vitro at pH 7.5, ADH1B*1 Km 0.013 mM and Vmax 5.2 per min; ADH1B*2 (rs1229984, His48) Km 1.8 mM and Vmax 190 per min; ADH1B*3 (rs2066702, Cys370) found almost exclusively in people of African origin. European carriers of ADH1B*2 eliminate ethanol about 14% faster. ALDH2 is a mitochondrial homotetramer with Km for acetaldehyde 0.2 µM; blood acetaldehyde is about 3 µM or less with active ALDH2 and 30 to 75 µM or higher in ALDH2*2 carriers. ALDH2*2 (rs671) has lysine at position 504 of the precursor (487 of the mature protein); a single ALDH2*2 subunit renders the tetramer nearly inactive; disulfiram inhibits ALDH2. rs671 allele frequency 0.160 in Han Chinese in Beijing, 0.271 in Southern Han Chinese, 0.240 in Japanese in Tokyo, 0.008 or less in the African, American, European and South Asian 1000 Genomes populations. Odds ratio for alcohol dependence 0.22 in ALDH2*2 heterozygotes (meta-analysis of 22 datasets).
Independent research
Brooks PJ, Enoch MA, Goldman D, Li TK, Yokoyama A. The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption PLoS Medicine, 2009.
doi:10.1371/journal.pmed.1000050 PubMed 19320537
Funding and finding
Funding
The authors received no specific funding for this article.
Finding
About 36% of East Asians show facial flushing, nausea and tachycardia after drinking, predominantly from ALDH2 deficiency; at least 540 million people, about 8% of the world population, are estimated to be ALDH2-deficient. In case-control studies from Japan and Taiwan, low-activity ALDH2 heterozygotes who drink have odds ratios of 3.7 to 18.1 for oesophageal squamous cell carcinoma after adjustment for alcohol consumption; ALDH2 deficiency does not influence oesophageal cancer risk in non-drinkers.
Independent research
Liebert A, López S, Jones BL, Montalva N, Gerbault P, Lau W, et al. World-wide distributions of lactase persistence alleles and the complex effects of recombination and selection Human Genetics, 2017.
doi:10.1007/s00439-017-1847-y PubMed 29063188
Funding and finding
Funding
EU Marie Curie ITN FP7 Framework Programme grant LeCHE (215362-2); Bicentennial Becas-Chile Scholarship, Chilean National Commission for Scientific and Technological Research (CONICYT); Annals of Human Genetics; MRC-DTA studentship.
Finding
Lactase persistence is associated with at least five independent functional single nucleotide variants in a transcriptional enhancer about 14 kb upstream of LCT: -13910*T (rs4988235), -13907*G (rs41525747), -13915*G (rs41380347), -14009*G (rs869051967) and -14010*C (rs145946881). -13910*T has almost reached fixation in some parts of Europe; the others occur at variable frequencies in the Middle East and Africa.
Independent research
Boyle EA, Li YI, Pritchard JK. An Expanded View of Complex Traits: From Polygenic to Omnigenic Cell, 2017.
doi:10.1016/j.cell.2017.05.038 PubMed 28622505
Funding and finding
Funding
This work was supported by RO1 HG008140, the National Science Foundation graduate research fellowship program and the Howard Hughes Medical Institute.
Finding
Perspective with new analysis. Fisher showed in 1918 that if many genes affect a trait, random sampling of alleles produces a continuous, normally distributed phenotype. Height illustrates the extreme polygenicity typical of many complex traits: across all SNPs genome-wide, the median SNP is associated with an effect of 0.14 mm on height, about one tenth of the median effect of genome-wide significant SNPs (1.43 mm). Under simplifying assumptions the authors estimate that more than 100,000 SNPs have independent causal effects on height. They propose an omnigenic model as a hypothesis.
Textbook or database
Chinnery PF. Primary Mitochondrial Disorders Overview GeneReviews, University of Washington, Seattle, 2021.
PubMed 20301403
Funding and finding
Funding
not stated in the chapter
Finding
Expert-authored, peer-reviewed overview, posted 8 June 2000, comprehensive update 29 July 2021. More than 70 polypeptides form the respiratory chain on the inner mitochondrial membrane. Mitochondrial DNA encodes 13 essential respiratory-chain subunits (seven of complex I, one of complex III, three of complex IV and two of complex V), two ribosomal RNAs (12S and 16S) and 22 transfer RNAs for intra-mitochondrial protein synthesis; the remaining respiratory-chain polypeptides and the proteins for respiratory-chain assembly, mitochondrial structure and mtDNA maintenance and expression are encoded by the nuclear genome. Each human cell contains thousands of copies of mtDNA; in heteroplasmy, mutated and wild-type mtDNA coexist, and the proportion of mutated mtDNA must exceed a critical threshold before a cell expresses a biochemical defect of the respiratory chain. mtDNA pathogenic variants are transmitted by maternal inheritance; offspring of males with an mtDNA pathogenic variant do not inherit it.
Independent research
Horsthemke B. A critical view on transgenerational epigenetic inheritance in humans Nature Communications, 2018.
doi:10.1038/s41467-018-05445-5 PubMed 30061690
Funding and finding
Funding
Work in the author's laboratory has been funded by the Deutsche Forschungsgemeinschaft.
Finding
Comment. Within a cell lineage, gene activity states are maintained over cell divisions; this cellular inheritance is attributed to regulatory feedback loops, chromatin modifications (DNA methylation and histone modifications) and long-lived non-coding RNAs. Chromatin is extensively reshaped during germ-cell differentiation and in totipotent cells after fertilisation. Transgenerational epigenetic inheritance in humans is a matter of controversial debate because genetic, ecological and cultural inheritance confound it; epidemiological links between grandparental food supply and grandchildren's health await independent replication; most families in which abnormal DNA methylation segregated with a rare disease proved to carry an underlying genetic variant; the excess cardiovascular and metabolic disease after prenatal exposure to the Dutch hunger winter is a direct consequence of exposure in utero, not germline transmission. The author concludes that the evidence is not (yet) conclusive.

Updated 2026-10-21