The following 2 papers are relevant to this discussion:
R.E. Hickson & R.L. Cann, "Mhc allelic diversity and modern human
origins", J.Mol.Evol. 45 (1997), 589-98.
T.F. Bergstrom, A. Josephson, H.A. Erlich & U. Gyllensten, "Recent
origin of HLA-DRB1 alleles and implications for human evolution", Nature
Genetics 18 (1998), 237-42.
They show that the vast majority of DRB alleles are relatively young
(order of magnitude: 250,000 years), consistent with other nuclear and
with mtDNA data, and indicate a population size of about 10^4
individuals for most of the last 1 million years. The previous
coalescence estimates ignored the DRB groups, the concentration of the
polymorphisms in exon 2, the coding sequences being under selection and
other problems. Of course, coalescence time estimates are extremely
imprecise.
Bergstrom et al.'s abstract:
"The HLA class I and class II loci are the most highly polymorphic
coding regions in the human genome. Based on the similarity of the
coding sequences of alleles between species, it has been claimed that
the HLA polymorphism is ancient and predates the separation of human
(Homo) and chimpanzee (Pan), 4-7.4 Myr ago. Analysis of intron
sequences, however, provides support for a more recent origin and for
rapid generation of alleles at the HLA class II DRB1 locus. The human
DRB1 alleles can be divided into groups (allelic lineages); most of
these lineages have diverged from each other before the separation of
Homo and Pan. Alleles within such a lineage, however, appear to be, on
average, 250,000 years old, implying that the vast majority (greater
than 90%) of the more than 135 contemporary human DRB1 alleles have been
generated after the separation of Homo and Pan. The coalescence time of
alleles within allelic lineages indicates that the effective population
size (Ne) for early hominids (over the last 1 Myr) was approximately
10^4 individuals, similar to the estimates based on other nuclear loci
and mitochondrial DNA. With a single exception, the genetic mechanisms
(gene conversion and point mutation) that have diversified the exon-2
sequences do not appear to extend into the adjacent intron sequences.
The part of exon 2 encoding the beta-sheet evolves in concert with the
surrounding introns, while the alpha-helix appears to have been
subjected to gene conversion-like events, suggesting that such exchange
events are highly localized and occur over extremely short sequence
tracts."
Furthermore, they write:
"The phylogenetic trees for primate exon-2 sequences... are consistent
with the notion that most of the alleles at some class II loci, such as
DRB1 and DPB1, may have a more recent origin [than previously believed]"
... "[S]tudies of human populations with a defined degree and time of
isolation (for example South American Indians) have provided support for
the view that new DRB1 alleles have been generated over the last
10,000-20,000 years."
"Given that coding sequences are subject to selection, they are
problematic for determining the evolutionary relationships and age of
alleles. Numerous studies have shown the polymorphism at HLA class I and
II loci to be under selection. For instance, the codons for amino acids
involved in binding of foreign peptides (antigen recognition site, ARS)
show an excess of replacement changes relative to silent changes, while
no such effect has been observed at the non-ARS codons, consistent with
diversifying selection. Furthermore, the polymorphism at several class
II loci, such as DRB1, is characterized by a 'patchwork' pattern of
amino-acid motifs, indicating that the alleles may have been generated
through sequence exchanges (that is, gene conversion-like events). This
implies that adjacent coding sequences may not share the same
evolutionary history and are therefore not suited to reconstructing
evolutionary relationships among alleles."
"The mean sequence difference among alleles within a lineage corresponds
to an average age of 180,000-320,000 years (range based on the standard
error). This implies that the vast majority of the more than 135
contemporary HLA-DRB1 alleles have a very recent origin." ... "Because
the ARS and non-ARS codons do not share the same evolutionary history,
... a realistic estimate of the age of alleles cannot be obtained using
exon sequences."
Hickson & Cann came to similar conclusions.
Furthermore, the HLA are the proteins presenting foreign peptides to the
immunity-generating system. If the parasites and other antigens humans
and other primates had to fend off were similar, we should expect
parallel evolution of their HLA epitope groups, which would simulate
erroneously low rates of diversifying evolution, and therefore too high
coalescence times.
Peter Ruest <pruest@dplanet.ch>
This archive was generated by hypermail 2b29 : Thu Nov 02 2000 - 14:27:55 EST