Nonneutral evolution of tandem repeats in the mitochondrial DNA control region of lagomorphs

Abstract

The mitochondrial DNA of the European rabbit (Oryctolagus cuniculus) contains a tandem array of 153-bp repeats in the vicinity of the replication origin of the H-stand. Variation among molecules in the number of these repeats results in inter- and intraindividual length polymorphism (heteroplasmy). Generally, in an individual, one predominant molecular type is observed, the others representing a low percentage of the mtDNA content. At the tissue level, we observe a particular distribution of this polymorphism in the gonads compared with liver, kidneys, or brain, implying a relationship between the differentiation status of the cells and the types of new mtDNA molecules which appear and accumulate during lifetime. Similar tandem repeats were also found in the mtDNA noncoding region of European hares (Lepus europaeus), a cottontail (Sylvilagus floridanus), and a pika (Ochotona rufescens). The lengths and the sequences of these units evolve rapidly and in a concerted way, but the number of repeats is maintained in a narrow range, and an internal 20-bp segment is highly conserved. Constraints restrict the evolution of the primary sequence of these repeated units, the number of which is probably controlled by a stabilizing selection.

Mitochondrial DNA variable number tandem repeats (VNTRs): utility and problems in molecular ecology

“…As mtVNTRs are frequently hypervariable, and drift (and/or selection) may rapidly change the frequencies of mtDNA polymorphisms (Koehler et al 1991;Jenuth et al 1997), different tissue types or body locations can contain significantly different frequencies or classes of mtVNTR. The distribution of mtDNA point mutations in mice (Jenuth et al 1997) and of mtVNTRs in rabbits (Casane et al 1994) have revealed that different tissue types contain variable allele frequencies which seem to be brought about by both drift and tissue-specific selection. Such tissue-specific mtDNA compositions also seem to play an important role in several human pathologies (Wallace 1994).…”

“…Wilkinson & Chapman (1991) studied mtVNTR copy-number changes in motherÐoffspring pairs of the evening bat Nycticeius humeralis and estimated a per generation mutation rate of 10 Ð2 . MotherÐoffspring pairs of European rabbits have been used to estimate a very similar (10 Ð2 ) per generation mutation rate (Casane et al 1994). Typical values for accumulation of mtDNA point mutations in humans have been thought to be in the order of 10 Ð6 Ð10 Ð8 (estimated from Brown et al 1979; Kondo et al 1993).…”

“…While slipped-strand mispairing and illegitimate elongation may produce the most frequent changes, copy-number changes may be less dramatic than intramolecular recombination which is known to cause large deletions in the Meloidogyne repeat arrays (Lunt & Hyman 1997) and may cause very rapid shifts in copy number. Although Casane et al (1994) have shown in the European rabbit that mtVNTR deletions of one repeat copy are more frequent than deletions of two, which are in turn more frequent than deletion of three repeats, many more pedigree and heteroplasmy studies are necessary to effectively characterize the nature of change typically observed in mtVNTRs. Once this information becomes available, however, it will allow us to greatly refine estimates of genetic divergence using mtVNTRs.…”

“…A frequent feature of many, but not all, control regions are short, tandemly repeated sequences, often predicted to fold into thermodynamically stable secondary structures. These repeats appear to be conserved in position across a range of (mostly mammalian) species and are hypothesized to be involved in the termination of transcription by nature of their complex secondary structure (Hoelzel et al 1995;Casane et al 1997;Wilkinson et al 1997). It is worth noting, however, that in all but a small number of species the control region is designated as such by virtue of its lack of coding structure rather than any direct evidence for replicative or transcriptional involvement, and thus should more correctly be designated ÔputativeÕ.…”

Peroxide accumulation without major mitochondrial alteration in replicative senescence

“…Rabbit articular chondrocytes were used for two reasons: morphologic changes of in vitro senescent cells are close to changes observed in degenerative articular pathologies found in old people [19]; rabbit mtDNA contains repeated sequences whose generation and maintenance suppose additions, deletions and rearrangements of units [20], furthermore a slight bias in their frequencies was observed in some tissues of old animals [21].…”