chr21·hg38·46.7 Mb

Chromosome 21

The smallest human autosome — a gene-poor, repeat-rich sliver of the genome whose very barrenness is what makes trisomy 21 the only autosomal trisomy routinely compatible with long-term survival.

Physical Properties

Length46.7 Mb

Centromeresubmetacentric

p-arm10.9 Mb

q-arm33.8 Mb

GC content41%

Genomic Features

Protein-coding genes234

Gene density5.0 / Mb

CpG islands3,098

EPIC v2 probes10,764

Notable

Largest geneDSCAM (840 kb)

Disease associations

Down syndrome

AML (RUNX1)

Amyotrophic lateral sclerosis (SOD1)

· Trisomy 21 (Down syndrome) — most common viable autosomal trisomy

· Smallest autosomal gene content (~230 coding genes)

· RUNX1 translocations are frequent in leukemia

Genomic Architecture

A single 7 Mb stretch on 21q contains only one gene — one of the largest gene deserts in the human genome

Three additional 1 Mb regions on 21q are completely devoid of genes

Together, these gene-poor regions comprise ~10 Mb, or approximately one-third of the euchromatic long arm

Deep Cuts

Trisomy 21 is lethal — just less so — Approximately 80% of trisomy 21 conceptions end in spontaneous abortion, mostly in the first trimester. The 20% that survive to birth represent a highly selected subpopulation. Among live-born trisomies, only trisomy …

The Down syndrome cancer paradox — DS individuals have a 500-fold increased risk of AMKL and a 20-fold increase in ALL, yet a significantly reduced risk of nearly all solid tumors (breast, lung, colon, melanoma). The "tumor suppressor trisomy" hypothes…

Chromosome 21 was the second chromosome fully sequenced — Published in Nature in May 2000 (Hattori et al.), chr21 was sequenced to near-completion one year after chr22. The chr21 sequence was a milestone for DS research, but it also revealed a surprise: only 127 known genes …

§ Deep dive

A single 7 Mb stretch on 21q contains only one gene — one of the largest gene deserts in the human genome

Three additional 1 Mb regions on 21q are completely devoid of genes

Together, these gene-poor regions comprise ~10 Mb, or approximately one-third of the euchromatic long arm

The gene deserts correspond to Giemsa-dark (G-band positive) regions with low GC content (L isochores, <43% GC), where gene density drops to ~1 per 300 kb

Ribosomal DNA arraysTandem repeats of the 45S rDNA unit (~13 kb per repeat, containing 18S, 5.8S, and 28S rRNA genes). The nucleolar organizer region (NOR) on 21p is one of five human NORs (on chr13, 14, 15, 21, 22)

Satellite DNAIncluding satellite 1, satellite 3, and beta-satellite sequences in the proximal short arm

No protein-coding genesThe entire short arm is repeat-derived and does not contribute to the euchromatic gene count

The T2T consortium's completion of all acrocentric short arms revealed that these regions are far more structured than previously thought, with segmental duplications shared between all five acrocentric chromosomes

Total repeat contentHigh, driven by the short arm satellite arrays

LINE-1 elementsEnriched in the gene-poor AT-rich regions of 21q — consistent with the general pattern of LINE accumulation in dark G-bands

Alu elementsDepleted relative to genome average, reflecting the low GC content of much of the chromosome

Large genes dominate available spaceDSCAM spans >840 kb, GRIK1 >400 kb, and several other genes exceed 200 kb. The oversized genes partially explain the low gene density — much of the euchromatic sequence is occupied by enormous introns