Shortly after the arrival of apes in Europe, global temperatures dropped sharply, marking a period of aridification and falling temperatures. In Africa, the cooler and more seasonal climate would have had the effect of contraction of equatorial forest and increasing seasonality in woodland habitats, and fossil apes are found not in forest but in seasonal woodland habitats. In Eurasia, the cooling resulted in an increasingly seasonal world in which dry/cold seasons were more extreme and longer 19. As a consequence, fruits that had been the primary food for apes, became hard to find during the cooler months. Evidence for intermittent (likely seasonal) starvation has been found at Pašalar in Turkey 20, and all ape colonies receded to small regions (refugia) until complete extinction occurred in Europe and Asia, approximately 8 Ma. Nevertheless, there is some evidence, based on the fossil record, that some of the European apes may have migrated back to Africa during this time 20-25.

Uricase mutation and its potential impact on human nutrition
The changing climate placed stress on the fossil apes, and rapid changes in genome occurred during this period 26, and there was a complete silencing of the uricase gene in the great ape and human clade 27, 28. The observation that a parallel mutation in uricase occurred somewhat later in Lesser Apes (Hylobatidae) during the late Miocene suggests the mutation provided selection (survival) advantage. The effects of the mutation were to shut down the gene and stop the production of the enzyme uricase 19, 27, the function of which is to break down uric acid.

Uric acid is a metabolic product of purine metabolism, and in most mammalian species, it is metabolized by the enzyme uricase (urate oxidase) to generate allantoin. However, in the great ape and human lineage (Hominidae), a progressive reduction in uricase activity occurred due to mutations in the promoter region followed by complete silencing of the gene from mutations in the coding region of codon 33 of exon 2 28. The genetic shutdown must have preceded the divergence of the orang utan, for the same mutation is present in this Asian great ape as well as the African apes and humans (Fig. 2). The consequence was a rise in serum urate, likely from levels of 1–2 mg dL−1 (based on measurement of uric acid in primates that still carry uricase) to levels of 3–4 mg dL−1 (based on studies of great apes and humans living on native (nonwestern) diets 29.

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Figure 2
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Phylogeny of apes and humans, showing the location of uricase mutation in the common ancestor of the great ape and human lineage and the independent mutation in the gibbon lineage later in time 38.
While several potential hypotheses have been forwarded for why an increase in serum urate may have been beneficial 30, 31, one of the stronger hypotheses is that it may have amplified the ability to store fat and glycogen from fruit sugar (fructose) 19. Recently, it has been shown that where fructose is the nutrient of choice, animals are able to increase their fat stores to protect them from periods where food is not available, such as during hibernation, long-distance migration or nesting 32. Fructose metabolism, unlike other nutrients, lowers energy levels in the cell, triggering adenine nucleotide degradation and uric acid formation that stimulate fat accumulation and insulin resistance 33, 34. The uricase mutation results in more uric acid formation in response to fructose, and this translates into higher blood pressure, a greater increase in liver fat and an increase in gluconeogenesis 28, 35, 36. The ability of the mutation to enhance the ability of fructose to generate fat creates a survival advantage that would be greater in temperate habitats in Eurasia, where dry/cold seasons would have been greater and longer. Thus, the uricase mutation, by amplifying the effects of fructose to increase fat stores, blood pressure and insulin resistance may have acted as a ‘thrifty gene’, providing survival advantage to fossil apes in seasonal habitats during times of food shortage 37.

However, in present human populations, the intake of fructose has increased markedly due to the introduction of refined sugar (sucrose) and the sweetener, high fructose corn syrup. As a consequence of increased sugar (fructose) intake as well as purine-rich foods, such as meat, serum urate is now between 3 and 12 mg dL−1, and those with the higher levels are at increased risk for developing type 2 diabetes, obesity, fatty liver and hypertension 38. Consistent with these findings, pilot clinical studies suggest reduction in fructose intake 39-41, or a lowering of serum uric acid, may improve features of metabolic syndrome, including blood pressure, insulin resistance, fatty liver and weight 42-44.

Evolutionary adaptations to famine are likely to affect nutrition and metabolic outcomes 29. On the other hand, the ‘weather hypothesis’ proposes that animals evolved to withstand periods of starvation by changing life history strategies to undergo regular periods of calorie restriction 45. By this means, lifespan could be maintained or even increased 46-48. For example, data on time spent hibernating in Turkish hamsters suggest that hibernation in small mammals retards biological ageing in proportion to the amount of time spent in the hibernating state 49. For animals that do not hibernate, periods of calorie restriction would be a regular feature in seasonal habitats, with animals losing more than half their body weight in winters, and the ‘weather hypothesis’ proposes that this is a biological or evolutionary strategy rather than necessity imposed by occupation of strongly seasonal habitats. As prolonged periods of fasting activate Nrf2 in animals 50 and man 51, it can be hypothesized that up-regulation of this anti-inflammatory cytoprotective transcription factor may contribute to the survival advantage in species that undergo fasting.

Early hominins: adaptations for bipedalism
The evolution of bipedalism has often been assumed to be due to leaving the shelter of forest and woodland and coming down to the ground, and it has been further assumed that upright posture was both a necessary pre-adaptation for bipedalism and itself an indication of its presence. The former may be true, but the latter is clearly not, for upright posture is present in many fossil apes that manifestly were not bipedal. Upright posture is seen in adaptations of the axial skeleton, such as reduction in lumbar vertebrae, broadening of the chest and long clavicle, and these are character states present in some later Miocene apes and all hominids, that is the great apes and humans. The earliest adaptations for bipedalism in human ancestry took place in deciduous woodlands, similar to those occupied by fossil apes for the 5 to 9 million years previous to the appearance of hominins 16, 17, 52, 53. Seasonal climates and diets composed largely of fruit were retained in the earliest hominins 18.

The present evidence suggests that adaptations of the hip and feet were amongst the earliest to change at 4-3Ma 54-57. Even after broadening of the ilium in Ardipithecus ramidus 58, the foot from the same individual 59 still retained a divergent and grasping big toe. Similarly, lengthening of the legs had not taken place in early hominins and the earliest evidence is on the australopithecine called ‘little foot’ at 3.6 Ma in South Africa 55, 56, where leg length exceeded arm length (Fig. 3). Human striding ability was not fully established until 1.8–2.0 Ma with the appearance of Homo erectus.