Beta-casein Protein

Beta-casein is a class of cow's milk protein that may provide effects beyond nutrition, due to the release of biologically active peptides on digestion (1). Beta-casein may be present as one of two major genetic variants: A1 and A2 (2). A2 beta-casein is recognised as the original beta-casein protein because it existed before a mutation caused the appearance of A1 beta-casein in European herds a few thousand years ago (3, 4).

The major difference between the A1 and A2 beta-casein proteins is a single amino acid at position 67 in a strand of 209 amino acids. A1 beta-casein has the amino acid histidine at position 67, while A2 beta-casein has a proline amino acid in the same position (Figure: 1). A1 beta-casein in cow's milk is different to other mammalian beta-caseins, because of its histidine at position 67. Human milk, goat milk, sheep milk and other species’ milk contain beta-casein which is ‘A2 like’, because they have a proline at the equivalent position in their beta-casein chains (5-7). The A1 beta-casein protein has been implicated as a potential etiological factor in type 1 diabetes mellitus, ischaemic heart disease and also as a modifier of behavioural symptoms associated with some neurological conditions such as autism. A2 beta-casein has not been implicated in these conditions (see the Science Overview page for details).


var-protein-chain
Figure 1: A1 and A2 beta-casein proteins showing the amino acid difference at position 67. This difference can be detected easily by a non-invasive DNA test which indicates accurately which beta-casein genes a cow carries.


A1 and A2 Beta-casein Genes

The bovine beta-casein gene is part of a cluster of 4 casein genes (alpha-S1-casein, alpha-S2-casein, beta-casein and kappa-casein) located on chromosome six (8). A1 and A2 are the most common beta-casein alleles (genetic variants) in dairy cattle, although other minor alleles exist (Figure: 2) (2, 4, 9). The A2 beta-casein gene is recognised as the progenitor of the beta-casein gene in the genus Bos, the genus of bovine animals to which cattle belong. As one gene is inherited from each parent, each cow can only carry two copies of the beta-casein gene but cows can, of course be homozygous or heterozygous for the A1 and/or A2 beta-casein allele. This, together with co-dominance, whereby one allele does not over-ride the other, means that a cow can only produce at most two types of beta-casein in its milk, and if she does carry two different alleles then the two forms will be produced in a 1:1 ratio.

var-evolution
Figure 2: Evolution of beta-caseins in cow’s milk from the original A2 type beta-casein. The same amino acid difference at position 67 occurs between the minor variants, so these sub-variants may be classified as 'A1 like' or 'A2 like'. 'A2 like' sub-variants include A3, D, E and possibly H and have a proline at position 67. 'A1 like' sub-variants include B, C, F, G and possibly H and have a histidine and share the capacity to produce BCM-7 with A1 beta-casein. [adapted from Formaggioni et al., 1999 (2)].

A2 beta-casein is found in all types of bovine animals, including all Western, African and Indian cattle and water buffalo. A1 beta-casein is carried by some cows of European breeds, all of which belong to the subspecies Bos taurus (10). However, the prevalence of the A2 and A1 beta-casein allele varies between cow herds and also between countries. For instance, a recent study on the beta-casein allele frequency in indigenous Indian cattle (Bos indicus) and river buffalo breeds (618 animals of 15 zebu cattle breeds and 231 buffaloes of 8 river buffalo breeds) reported 99 to 100% presence of the A2/A2 genotype in its indigenous cow (0.987) and buffalo (1.00) breeds (11). The same study also reported an absence of the A1/A1 genotype, thus in Indigenous Indian cow and buffalo breeds, nearly all animals are homozygous for the A2 beta-casein allele. Turning to European breeds, the Holstein, which is the most common dairy cow breed in Australia, Northern Europe and the US, carries the A1 and A2 beta-casein alleles in approximately equal distribution. Jersey herds typically have an A2 allele frequency somewhat higher than this, but with considerable between-herd variation. Also, some Jersey cows carry the “B” beta-casein allele which has been shown to give an even higher release of BCM7 (12). The Guernsey breed has an A2 beta-casein allele frequency of more than 90% (13).

References

  1. Phelan M, Aherne A, FitzGerald R.J, O’Brien N.M, (2009). Casein-derived bioactive peptides: Biological effects, industrial uses, safety aspects and regulatory status. International Dairy Journal. 19(11), 643–54. External link
  2. Formaggioni P, Summer A, Malacarne M, Mariani P, (1999). Milk protein polymorphism : Detection and diffusion of the genetic variants in Bos genus Parma: Universiti degli Studi de Parma, Annalli della Facolta di Medicina Veterinaria. External link.
  3. Ng-Kwai-Hang K,F. Grosclaude F, (2002). Genetic polymorphism of milk proteins. In: Fox PFaM, P.L.H editor. Advanced Dairy Chemistry: Volume 1: Proteins, Parts A&B. New York: Kluwer Academic/Plenum Publishers. p. 739-816. External link.
  4. Kaminski S, Cieslinska A, Kostyra E, (2007). Polymorphism of bovine beta-casein and its potential effect on human health. J Appl Genet. 48(3), 189-98. External link.
  5. Lonnerdal B, Bergstrom S, Andersson Y, Hjalmarsson K, Sundqvist A,K. Hernell O, (1990). Cloning and sequencing of a cDNA encoding human milk beta-casein. FEBS Lett. 269(1), 153-6. External link.
  6. Provot C, Persuy M.A, Mercier J.C, (1989). Complete nucleotide sequence of ovine beta-casein cDNA: inter-species comparison. Biochimie. 71(7), 827-32. External link.
  7. accession e. Goat beta-casein [cited 2011 3 October]. External link.
  8. Rijnkels M, (2002). Multispecies comparison of the casein gene loci and evolution of casein gene family. J Mammary Gland Biol Neoplasia. 7(3), 327-45. External link.
  9. Farrell H.M Jr., Jimenez-Flores R, Bleck G.T, Brown E.M, Butler J.E, Creamer L.K, et al. (2004). Nomenclature of the proteins of cows' milk--sixth revision. J Dairy Sci. 87(6), 1641-74. External link.
  10. Woodford K, (2007). Devil in the Milk: Illness, Health and Politics: A1 and A2 Milk. Wellington New Zealand: Craig Potton Publishing. External link.
  11. Mishra B.P, Mukesh M, Prakash B, Sodhi M, Kapila R, Kishore A, et al. (2009). Status of milk protein, ß-casein variants among Indian milch animals. Indian Journal of Animal Sciences.79(7), 722-5. External link.
  12. De Noni I, (2008). Release of b-casomorphins 5 and 7 during simulated gastro-intestinal digestion of bovine b-casein variants and milk-based infant formulas. Food Chemistry. 110(4), 897-903. External link.
  13. Scientific Report of EFSA prepared by a DATEX Working Group on the potential health impact of beta-casomorphins and related peptides. EFSA Scientific Report (2009) 231, 1-107 [cited 3 October 2011]. External link.