In the last few years, the phylogeography of many clades of the human mtDNA and Y-chromosome systems has been adequately resolved, but there still exist several big remaining puzzles.
The first one is that of mtDNA haplogroup X, which has been addressed in a recent paper. This is a very ancient clade, which is found at low frequencies almost everywhere, and is divided into two subclades: X1 is found mainly in eastern and northern Africa, whereas X2 is found in northern Africa and everywhere else, including Native Americans. It is interesting that the X2 seems to have spread after the Last Glacial Maximum, and the Native American clade, X2a was an "early split": today's Siberian X2 seem to be recently derived from Western Eurasia than those of the ancient trek which brought X2 into the New World. It is fascinating that X2 was brought into the New World by some ancient expansion that did not leave any traces in the genes of modern inhabitants of the likely routes.
The second great puzzle is mtDNA haplogroup M1 which occurs in East and North Africa, West Asia and Southern Europe, but not apparently anywhere else. M1 is a branch of the mainly Asian macrohaplogroup M, which is of great antiquity in Asia and likely originated there. According to a recent abstract, Holden et al. indicate that M1 is found at high frequencies in East and Northern Africa but not in Sub-Saharan Africa, and hint that it may be linked to the Afro-Asiatic language family. This suggestion is reasonable, and in my opinion the correspondence between M1 and Y-chromosome haplogroup E3b is quite remarkable throughout the broad peri-Mediterranean region, with E3b also reaching high frequencies in Afro-Asiatic speakers.
The third puzzle is that of Y-chromosome haplogroup DE defined by the YAP mutation. The E clade of YAP encompasses the great majority of African Y-chromosomes, and is clearly split into a subclade, E3b which has a peri-Mediterranean distribution similar to that of the aforementioned M1, and all the rest, almost exclusively limited to Sub-Saharan Africa. The "brother" of E, is haplogroup D, which is found in such peoples as the Andamanese, the Tibetans, and the Ainu. At present it seems reasonable that E originated somewhere in Africa, but the origin of D is far from certain, as it is now found in certain "fringe" populations, but also in low frequencies among many Asians. Perhaps, D had a much more prevalent distribution in the past, but the expansion of later successful lineages, such as O, the main haplogroup found in East Asians today overwhelmed those earlier Asian populations. What about YAP itself? Dit it originate in Asia, where its D descendants are located, or in Africa, where its E descendants are? As late as 2003, we don't know, and no new research has appeared to shed light on this problem.