Our molecular estimate of the age at which occurred the split of the main lineages of Murinae fits completely with the paleontological evidence, which indicates that the different modern lineages probably arose around 11 Ma. At that time, the first Progonomys and Karnimata are reported outside the Siwalik region, in Eurasia and Africa and the modern lineages such as the Apodemus lineage arose in Europe. The tribe Murini diverged from the Praomyini at 9.85 Ma /10.84 Ma with an overlapping CI interval of 12.46 to 8.64 Ma. The divergence of the different Murini subgenera including Malpaisomys took place at 6.94 /6.93 /8.6 25.4 Ma ). We are confident in these estimates because they are highly congruent between the two approaches but also with previous molecular studies and with the oldest Murini representatives found in the fossil record of the Siwalik: Mus auctor and Mus sp.. Consequently, the colonization of the Canary ALK5 Inhibitor II Islands could have occurred anytime after 6.9 Ma. However, since there is no paleontological evidence for the presence of Malpaisomys or its predecessor on the Canary Islands or on the continent previous to the Pleistocene, it is difficult to propose a date of arrival and a place for the Fulvestrant clinical trial origin of the lava mouse. As the oldest Malpaisomys fossils are ca. 30,000 years old, its first occurrence predates the first human settlement. Thus, the hypothesis that a North African ancestor reached the eastern Canary Islands after 6.9 Ma ago during a major sea level regression via natural rafts is likely. Further phylogenetic investigations are now needed to corroborate this hypothesis and to determine whether the colonization of the Canary archipelago by terrestrial mammals corresponded to a single event or not. Investigating the phylogeny of the two other endemic extinct rodents, Canariomys, could also shed new light on this question. For the first time ancient DNA sequences show that Malpaisomys was more closely related to the genus Mus than to any other Murinae, a hypothesis that has never been investigated with morphological data. Further investigations are now needed to solve the inter-specific relationships among the Malpaisomys/mouse species clade. Such results will help to clarify whether Malpaisomys is embedded among the genus Mus and will have taxonomic implications for the whole group. Indeed, they will help to decipher if the mouse subgenera as currently defined should be elevated to the rank of genus as already suggested. They will also help to refine the timing of the colonization of the Canaries by the Malpaisomys ancestor and to elucidate the route taken to reach the archipelago. Annexins form a family of peripheral membrane proteins that can coordinate Ca2+ ions via conserved a-helical repeats.