RECENT FINDINGS:? THE CURRENTLY ACTIVE HUMAN L1 HAS REDUCED THE GENETIC FITNESS OF HUMANS - We earlier showed that the human-specific L1Hs family (also called L1Pa1, or Ta) evolved from the ancestral L1Pa2 family soon after the human / chimpanzee divergence, about 6 Myr ago and remains active in present humans. We summarized our findings showing that this L1 family is reducing the fitness of present day humans in our 2006 annual report. This study was published early in 2006 and the reference is given below.? HUMAN POPULATION GENETIC STRUCTURE AND DIVERSITY INFERRED FROM POLYMORPHIC L1 INSERTIONS - We had earlier cloned the Ta1-containing loci from four ethnic groups: African pygmy, Caucasian Druze, Chinese, Melanesian. We used these L1 inserts to augment those in the human genome database to robustly analyze human population structure and origins using just L1 insertions. This study was also published in 2006 and is referenced below. ? USING THE DIVERGENCE OF L1 INSERTS TO DETERMINE THE MUTATION RATE - An important issue in biology is the factors that affect mutation rate, generally taken as the base substitution rate of sequences not under natural selection (i.e., neutrally evolving sequences). We estimated this rate from the accumulation of base substitutions by 30,000 distinct and assuredly neutral orthologous sequences in human, chimpanzee, and macaque DNA. These orthologues are the L1 inserts of six different L1 families that went extinct at different times between 6 and 53 million years ago in the common ancestor of these species. Thus the L1 orthologues had resided in the common ancestor for different lengths of time. Nonetheless, as orthologous inserts are identical by descent, any pair of chimpanzee and human L1 orthologues should reflect only the mutations that accumulated since these species diverged 4-7 MYA (and any surviving ancestral polymorphisms). However, L1 orthologue-pairs from the older families accumulated significantly fewer mutations than the younger ones. As the hypermutable CpG dinucleotides were excluded from the divergence measurements, the higher mutation rate experienced by the younger L1 orthologues was not due to mutation of these dinucleotides. However, we found that more of the CpGs of the older L1 sequences had been converted to their non-CpG counterparts than occurred in the younger L1 families. Thus, the extent of orthologue divergence was a function of their CpG, but not total (C + G), content. A possible explanation is that mismatches involving CpG sites recruit error prone mismatch repair polymerases that cause mutations in contiguous normally base paired DNA. Whatever the explanation, excluding CpG sites from divergence calculations is not sufficient to account for their effect on mutation rates, an effect that could confound the correlations of mutation rate with commonly invoked factors as generation time and transcriptional activity.
| Boissinot, Stephane; Davis, Jerel; Entezam, Ali et al. (2006) Fitness cost of LINE-1 (L1) activity in humans. Proc Natl Acad Sci U S A 103:9590-4 |
| Witherspoon, D J; Marchani, E E; Watkins, W S et al. (2006) Human population genetic structure and diversity inferred from polymorphic L1(LINE-1) and Alu insertions. Hum Hered 62:30-46 |
