Lessons from the bovine genome: implications for human nutrition and research.

Nearly 10,000 years ago, humans began to domesticate cattle for their ability to transform grass into energy-dense meat and milk. It is impossible to estimate all of the consequences of this decision to the subsequent development and success of human civilization, yet it is clear that humans and cattle have become inexorably linked. The influence of bovine milk to human nutrition is highlighted by the convergent evolution of lactase persistence; in separate pastoral human populations, DNA mutations that enabled individuals to drink milk into adulthood were so advantageous that they became the dominant polymorphism (1). The bovine genome (2) and bovine HapMap (3) papers recently published in Science represent the first fruits of an impressive collaboration of .300 scientists from 25 countries. These projects, which include the sequencing and analysis of the bovine genome as well as the genotyping of diverse cattle breeds, have established an unprecedented knowledge base for research in fields such as immunology, lactation, and ruminant physiology. For agriculture, these projects provide the data necessary to improve the efficiency of the cattle and dairy industries to feed the world’s population. Specifically, these data enable the identification of genetic variants in cattle affecting milk production, reproduction, energy efficiency, and disease resistance and guide the selection of high-performing individuals in cattle breeding programs. Even more exciting for nutrition scientists, the bovine genome represents a breakthrough for the study of milk and lactation. Paired with preexisting extensive bovine milk and lactation data, the bovine genome sequence is a key passage on a modern Rosetta stone. Just as comparative translation of languages on the Rosetta stone enabled the interpretation of Egyptian hieroglyphics, comparative genomics with the addition of the bovine genome enables the identification of milk and lactation-related genes across all sequenced mammalian genomes. In a companion paper to the bovine genome paper (2), lactation-specific data are linked for the first time with the genomic sequences of 7 mammalian species—human, mouse, rat, dog, cow, opossum, and platypus—to better understand the molecular evolution of milk and lactation (4). Why study the evolution of milk and lactation? Milk uniquely informs us about nutrition, because it is the only food evolved specifically to nourish mammals. Because milk is produced for the offspring at the expense of the mother, it can be theorized that few superfluous components would be present in milk. Generation after generation, individuals able to produce more nourishing milk propagate their genes by their offspring’s survival and reproductive success. Thus, the genes of milk production provide a blueprint for nourishment. Although it is well known that milk composition is highly variable across species (5), the bovine lactation study revealed that milk and mammary genes are more likely to be present and more conserved in all mammals than are other genes in the genome (4). The integrity of lactation has been critical to Mammalia and as these species diverged, milk remained their unifying resource. Indeed, milk-related genes were found to be evolving more slowly, on average, along the bovine lineage than other genes in the bovine genome and none of the milk or lactation genes were statistically fast evolving (4). Thus, the ingredients in mammalian milk have been set over millions of years and should therefore serve as an accurate guide to neonatal nutritional requirements. What are the unifying nutritional functions of milk? First, milk, being the sole source of nourishment during the neonatal period, contains all of the essential nutrients required for the growing neonate. Second, milk is not simply a soup of individual nutrients; rather, it is an ensemble of biomolecules in complex, higher-order structures. The most abundant milk proteins are delivered as micelles, fat is delivered as milk fat globules, and glucose is delivered as the disaccharide lactose. All of these structures influence bioavailability and the rate at which these nutrients are delivered to blood and tissues (6). Third, milk contains an arsenal of protective molecules and specialized cells to directly combat pathogens and to guide the development of the infant’s immune system (7). Fourth, milk contains oligosaccharides not digestible by the infant but that do promote a select subset of protective bacteria in the infant’s gut (8). Fifth, milk contains signaling compounds that regulate the development of the offspring with effects on metabolic regulation, hormone sensitivity, and neurological pathways, many of which persist into adulthood (9). In summary, the guiding principles for nutrition research are that foods have the capacity to provide essential nutrients, regulate bioavailability via biomolecular structure, modulate immune function, direct gut microbiota, and influence developmental signaling, all of which are exemplified by milk. 1 Author disclosures: D. G. Lemay, M. Rijnkels, and J. B. German, no conflicts of interest. * To whom correspondence should be addressed. E-mail: dglemay@ucdavis. edu.