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Other artiodactyls include camels, cattle, deer and pigs, although hippopotamuses are not closely related to these groups. The Hippopotamidae are believed to have evolved in Africa; the oldest known hippopotamid is the genus Kenyapotamus, which lived in Africa from 16 to .

The suggested subspecies were never widely used or validated by field biologists; the described morphological differences were small enough that they could have resulted from simple variation in nonrepresentative samples. While hippopotamid species spread across Asia and Europe, no hippopotamuses have ever been discovered in the Americas, although various anthracothere genera emigrated into North America during the early Oligocene. Taxonomists disagree whether or not the modern pygmy hippopotamus is a member of Hexaprotodon – an apparently paraphyletic genus, also embracing many extinct Asian hippopotamuses, that is more closely related to Hippopotamus – or of Choeropsis, an older and basal genus.

Genetic analyses have tested the existence of three of these putative subspecies. Three species of Malagasy hippopotamus became extinct during the Holocene on Madagascar, one of them within the past 1,000 years.

A study examining mitochondrial DNA from skin biopsies taken from 13 sampling locations, considered genetic diversity and structure among hippo populations across the continent. The Malagasy hippos were smaller than the modern hippopotamus, likely through the process of insular dwarfism.

This secretion is initially colourless and turns red-orange within minutes, eventually becoming brown.

Two distinct pigments have been identified in the secretions, one red (hipposudoric acid) and one orange (norhipposudoric acid). They inhibit the growth of disease-causing bacteria, and their light absorption peaks in the ultraviolet range, creating a sunscreen effect.

The hippopotamus is among the most dangerous animals in the world as it is highly aggressive and unpredictable. A rough evolutionary lineage can be traced from Eocene and Oligocene species: Anthracotherium and Elomeryx to the Miocene species Merycopotamus and Libycosaurus and the very latest anthracotheres in the Pliocene.

Pliny the Elder writes that, in his time, the best location in Egypt for capturing this animal was in the Saite nome; Hippos are still found in the rivers and lakes of the northern Democratic Republic of the Congo, Uganda, Tanzania and Kenya, north through to Ethiopia, Somalia and Sudan, west to The Gambia, and south to South Africa.

Genetic evidence suggests that common hippos in Africa experienced a marked population expansion during or after the Pleistocene, attributed to an increase in water bodies at the end of the era.

These findings have important conservation implications as hippo populations across the continent are currently threatened by loss of access to fresh water.

The pygmy hippopotamus belongs to a different genus in Hippopotamidae, either Choeropsis or Hexaprotodon. Further, some taxonomists group hippopotamuses and anthracotheres in the superfamily Anthracotheroidea. Their common ancestor would have lived in the Miocene, about .

Hippopotamidae are sometimes known as hippopotamids. Hippopotamidae are classified along with other even-toed ungulates in the order Artiodactyla. Hippopotamids are therefore deeply nested within the family Anthracotheriidae.

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