The tau (MAPT) locus exists as two distinct clades, H1 and H2. The H1 clade has a normal linkage disequilibrium structure and is the only haplotype found in all populations except those derived from Caucasians. The H2 haplotype is the minor haplotype in Caucasian populations and is not found in other populations. It shows no recombination over a region of 2 Mb with the more common H1 haplotype. The distribution of the haplotype and analysis of the slippage of dinucleotide repeat markers within the haplotype suggest that it entered Homo sapiens populations between approx. 10000 and 30000 years ago. However, sequence comparison of the H2 haplotype with the H1 haplotype and with the chimp sequence suggests that the common founder of the H1 and H2 haplotypes was far earlier than this. We suggest that the H2 haplotype is derived from Homo neanderthalensis and entered H. sapiens populations during the co-existence of these species in Europe from approx. 45000 to 18000 years ago and that the H2 haplotype has been under selection pressure since that time, possibly because of the role of this H1 haplotype in neurodegenerative disease.
- H2 haplotype
- Homo sapiens
- human genetics
- MAPT gene
- Neanderthal man
Homo sapiens and Homo neanderthalensis lineages diverged approx. 500000 years ago . The latter were the sole human colonizers of Europe until approx. 45000 years ago when H. sapiens also came to Europe . H. neanderthalensis was still present in Europe approx. 18000 years ago . There has much debate about whether H. sapiens and H. neanderthalensis ever mated or whether the former merely displaced the latter from Europe over this time frame . From a genetic perspective, this debate has been limited because the only DNA evidence directly available has been mitochondrial  and, although this clearly indicates no contribution to the H. sapiens mitochondrial genome, one cannot generalize from this limited information to autosomal loci, particularly for genes that may have been subjected to selection pressure .
The tau (MAPT) locus is very unusual. Over a region of approx. 1.8 Mb, there are two haplotype clades in European populations, H1 and H2 [6,7]. In other populations, only the H1 occurs and shows a normal pattern of recombination [8,9]. This locus contains several other genes besides MAPT  (see Figure 1). The H2 haplotype shows remarkably little genetic variation and differs from the H1 haplotype in both sequence and in terms of the orientation of several elements of the locus (Figure 2). These differences prevent recombination between the heterologous clades [10,11].
We have been interested in the MAPT locus because it is a susceptibility locus for diseases with tangles, including progressive supranuclear palsy  and corticobasal degeneration , and possibly also including Parkinson dementia complex of Guam , a devastating epidemic tangle disease which, at one time, was the major cause of death in South Guam, but has now virtually disappeared [14–16].
Analysis of the sequences on the H1 and H2 backgrounds, and comparison of these sequences with those of the chimp (Pan troglodytes) sequence show that, while both H1 and H2 sequences are more similar to each other than to the chimp sequence, they do not follow a predictable relationship: at some sequences, the chimp sequence is similar to H1 and at others, it is similar to H2 (see Table 1, and also [17,18]). Thus the H1 and H2 sequences do not follow a precursor–product relationship and one cannot be derived directly from the other, rather both must have been derived independently from a more distant precursor. Logically, therefore their relationship must be as illustrated in Figure 3.
We have two means to date the origin of the H2 haplotype: first, by its geographical distribution, which is consistent with its intrusion into the H. sapiens population at around the time of the founding of the European population , approx. 30000 years ago and, secondly, by assuming that the founding event was a single incident, by the slippage of microsatellite repeat markers [19,20]. The analysis of the slippage of microsatellite markers is given in Table 2 and is consistent with a last common ancestor in the time range of this founding. In addition, extensive sequencing of H2 homozygotes has yielded very few polymorphisms in contrast with the large number of variants found exclusively in the H1 clade [20a].
H. sapiens and H. neanderthalensis co-existed in Europe from approx. 45000 to 18000 years ago . We suggest that a plausible explanation for the ingress of the H2 haplotype is that an ancestral H. neanderthalensis allele, consistent with the parsimony tree of Figure 3, entered the European H. sapiens genome during the period of co-existence, and has spread through selection pressure to its current allele frequency of approx. 25% in this population . The H2 allele is protective against two rare diseases: progressive supranuclear palsy and corticobasal degeneration [6,12]. However, MAPT may also be a susceptibility locus for Parkinson's dementia complex of Guam , a disease that reached epidemic proportions around the end of the Second World War and was a major cause of death on the island at that time [14,15]. Thus, while we consider neurodegenerative tangle diseases as rare curiosities, it remains possible that these diseases, like kuru , can reach prevalences at which they exert strong selection pressures. In this regard, it is worth noting that both von Economo disease (the sleepy sickness epidemic of Parkinsonism after the Spanish flu epidemic of 1919) , and subacute sclerosing panencephalitis, a currently rare but frequently fatal complication of measles infection , are also diseases with tangle pathology.
Clearly, in the absence of MAPT sequence data from H. neanderthalensis, these suggestions are speculative. However, they suggest that the search for other genetic remnants of H. neanderthalensis should concentrate on regions with low-recombination rates in European populations in which the sequence diversity is great, as it is here. Interestingly, a recent assessment of LD (linkage disequilibrium) across the genome in different populations suggested that the MAPT locus was the longest region of LD in Europeans .
Molecular Mechanisms of Neurodegeneration: Joint Biochemical Society/Neuroscience Ireland Focused Meeting (and Satellite Symposium) held at O'Reilly Hall, University College Dublin, Republic of Ireland, 14–16 March 2005. Organized by D. Walsh (University College Dublin, Republic of Ireland), V. Campbell (Trinity College Dublin, Republic of Ireland), M. Fitzgibbon (Trinity College Dublin, Republic of Ireland), B. Irvine (Queen's University Belfast, Northern Ireland), T. Lynch (University College Dublin, Republic of Ireland), J. Johnston (Queen's University Belfast, Northern Ireland), C. O'Neill (University College Cork, Republic of Ireland) and M. Farrell (Royal College of Surgeons in Ireland, Dublin, Republic of Ireland). Edited by C. O'Neill and B. Irvine.
Abbreviations: LD, linkage disequilibrium
- © 2005 The Biochemical Society