Origin of human chromosome 2: an ancestral telomere-telomere fusion.

Abstract

We have identified two allelic genomic cosmids from human chromosome 2, c8.1 and c29B, each containing two inverted arrays of the vertebrate telomeric repeat in a head-to-head arrangement, 5'(TTAGGG),,-(CCCTAA),,3'. Sequences fln g this telomeric repeat are characteristic of present-day human pretelomeres. BAL-31 nuclease experiments with yeast artificial chromosome clones of human telomeres and fluorescence in situ hybridization reveal that sequences flanking these inverted repeats hybridize both to band 2q13 and to different, but overlapping, subsets of human chromosome ends. We conclude that the locus cloned in cosmids c8.1 and c29B is the relic of an ancient telomeretelomere fusion and marks the point at which two ancestral ape chromosomes fused to give rise to human chromosome 2.Similarities in chromosome banding patterns and hybridization homologies between ape and human chromosomes suggest that human chromosome 2 arose out of the fusion of two ancestral ape chromosomes (1-3). Molecular data show evidence that this event must have occurred only a few million years ago (refs. 4 and 5 and the references therein). Although the precise nature of this putative fusion is unknown, cytogenetic data point to either a centromeric or telomeric fusion in the vicinity of region 2ql (1, 2, and 6). The observation that telomeric DNA is present in chromosomal band q13 suggests that telomeres, the extreme ends of chromosomes, may have been involved in this fusion (7,8). Normally, telomeres form a dynamic buffer against loss of internal sequence and prevent chromosomes from fusing (for review, see ref. 9). By contrast, nontelomeric DNA ends are subject to degradation by nucleases and to fusion by ligation (10,11).The termini of human chromosomes consist of head-to-tail tandem arrays ofTTAGGG, running 5'--3' toward the end of the chromosome, with average lengths of 5-10 kilobases (kb) in somatic cells (7,12,13). The proximal ends of these arrays contain degenerate forms of this repeat, such as (TTGGGG), and (TGAGGG)J, (14). Sequences adjacent to these simple repeats have been characterized in a number of human chromosomes and shown to consist of repetitive elements, each shared by a subset of all chromosomes (13,(15)(16)(17). In addition, stretches of telomeric repeats are present at interstitial sites, usually in subtelomeric regions but also at a distinct internal site within band 2q13 (8). We describe here the architecture of the sequence at this internal locus at 2q13, which represents a relic of the fusion of two ancestral ape chromosomes in the evolution ofhuman chromosome 2. 11 MATERIALS AND METHODS Library Screening. Approximately 1.4 x 106 colonies from a human genomic cosmid library containing Mbo I partial digestion fragments of 35-41 kb in vector pWE15, propagated in host NM554 (Stratagene), were screened with pSC4, a human genomic 300-base-pair (bp) Alu I fragment present at the subtelomeric regions offive different chromosomes, as well as at a single nonterminal locus at 2q13, described elsewhere (8). ...

The origin of human chromosome 2 analyzed by comparative chromosome mapping with a DNA microlibrary

“…Thus, the centromere of human chromosome 2 should have been derived from a chromosome similar to PTR 12 or PPA 12, while the centromere from the chromosome similar to PTR 13 or PPA 13 was inactivated or lost (Dutrillaux 1979). This hypothesis is supported by Analysis of human chromosome 2 with a DNA microlibrary recent in situ hybridization experiments with centromere and telomere DNA sequences of human chromosome 2 (Wells et al 1990, Ijdo et al 1991, Avarello et al 1992, Baldini et al 1993. Close to the assumed fusion point (2q13) a relict of an alphoid domain was found by in situ hybridization of a satellite DNA clone under low hybridization stringency (Avarello et al 1992, Baldini et al 1993).…”

“…This alphoid domain may indicate the presence of the inactivated centromere in human band 2q21. In addition, proximal to 2q21, telomeric sequences were found in band 2q13 by in situ hybridization of DNA probes containing inverted arrays of the vertebrate telomeric repeat in a head-to-head arrangement (Wells et al 1990, Ijdo et al 1991. This band should therefore represent the fusion point of the telomeres of the two primate homologs.…”

The human TTAGGG repeat factors 1 and 2 bind to a subset of interstitial telomeric sequences and satellite repeats

“…In humans, three classes of ITSs were identified [15]: (i) subtelomeric ITSs, located within subtelomeric domains and composed of extended arrays (usually several hundreds of base pairs), including many degenerate units; they probably arose from recombination events involving chromosome termini [16]; (ii) short internal ITSs, located away from telomeres and composed of relatively few TTAGGG units; these ITSs are likely to have been generated during the repair of DNA double-strand breaks that occurred during evolution [17]; (iii) one fusion ITS, located in 2q14, derived from the end fusion between the two ancestral chromosomes that gave rise to human chromosome 2 [18]. No clear indication of any particular function of ITSs has been provided so far.…”

iSAX: disk-aware mining and indexing of massive time series datasets

“…Of course, it has been suspected that that human chromosome 2 is a recent species-specific fusion of two ancestral primate chromosomes for several decades (Ijdo et al 1991). More recent studies (Rogers et al 2006) have confirmed that the mapping above is correct, and the section that the rhesus macaque 12 and 13 maps to are called 2q and 2p, respectively.…”

“…It is merely a very large dataset for which we can obtain ground truth by other methods (Ijdo et al 1991;Rogers et al 2006).…”