On 2016 Apr 06, Donald Forsdyke commented:

PROTEIN SIZE AND CONCENTRATION DETERMINE DOSAGE-SENSITIVITY?

With the goal of understanding “the evolution of incomplete sex chromosome dosage compensation mechanisms in general,” the authors confirm that, among dosage-sensitive genes, those whose products specifically engage in stoichiometric complexes with other gene products, have a high degree of dosage-compensation. However, most genes are not dosage-limited by stoichiometry and “perplexing questions” remain. It is suggested that “certain loci … simply lack dosage effects” (my italics). In other words, certain loci “simply” contribute more to dosage effects than others.

While far from simple, this proposal is consistent with dosage compensation being more concerned with collective protein functions than with the specific functions of individual proteins (1). In the crowded cytosol the protein collective should exert an entropy-driven aggregation pressure on individual proteins, as part of a process of intracellular self/not-self discrimination (2). It is predicted that small, low concentration, proteins, will hardly influence aggregation pressure, so here there is no necessity for dosage compensation between the sexes. However, large, high concentration, proteins will greatly influence aggregation pressure, so here regulation of dose, on a gene-by-gene basis or otherwise, should be critical. Failure to regulate such dosage in human females would explain their susceptibility to autoimmune diseases (3-5).

1.Forsdyke DR (1994) Relationship of X chromosome dosage compensation to intracellular self/not-self discrimination: a resolution of Muller's paradox? J Theor Biol 167:7-12. Forsdyke DR, 1994

2.Forsdyke DR (2009) X chromosome reactivation perturbs intracellular self/not-self discrimination. Imm Cell Biol (2009) 87:525-528.Forsdyke DR, 2009

3.Dillon SP et al. (2012) Sex chromosome aneuploidies among men with systemic lupus erythematosus. J Autoimmun 38:J129-J134. Dillon SP, 2012

4.Forsdyke DR (2012) Ohno's hypothesis and Muller's paradox: sex chromosome dosage compensation may serve collective gene functions. BioEssays 34:930-933. Forsdyke DR, 2012

5.Wang J et al. (2016) Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X. Proc Natl Acad Sci USA doi/10.1073/pnas.1520113113 Wang J, 2016

On 2016 Apr 06, Donald Forsdyke commented:

PROTEIN SIZE AND CONCENTRATION DETERMINE DOSAGE-SENSITIVITY?

With the goal of understanding “the evolution of incomplete sex chromosome dosage compensation mechanisms in general,” the authors confirm that, among dosage-sensitive genes, those whose products specifically engage in stoichiometric complexes with other gene products, have a high degree of dosage-compensation. However, most genes are not dosage-limited by stoichiometry and “perplexing questions” remain. It is suggested that “certain loci … simply lack dosage effects” (my italics). In other words, certain loci “simply” contribute more to dosage effects than others.

While far from simple, this proposal is consistent with dosage compensation being more concerned with collective protein functions than with the specific functions of individual proteins (1). In the crowded cytosol the protein collective should exert an entropy-driven aggregation pressure on individual proteins, as part of a process of intracellular self/not-self discrimination (2). It is predicted that small, low concentration, proteins, will hardly influence aggregation pressure, so here there is no necessity for dosage compensation between the sexes. However, large, high concentration, proteins will greatly influence aggregation pressure, so here regulation of dose, on a gene-by-gene basis or otherwise, should be critical. Failure to regulate such dosage in human females would explain their susceptibility to autoimmune diseases (3-5).

1.Forsdyke DR (1994) Relationship of X chromosome dosage compensation to intracellular self/not-self discrimination: a resolution of Muller's paradox? J Theor Biol 167:7-12. Forsdyke DR, 1994

2.Forsdyke DR (2009) X chromosome reactivation perturbs intracellular self/not-self discrimination. Imm Cell Biol (2009) 87:525-528.Forsdyke DR, 2009

3.Dillon SP et al. (2012) Sex chromosome aneuploidies among men with systemic lupus erythematosus. J Autoimmun 38:J129-J134. Dillon SP, 2012

4.Forsdyke DR (2012) Ohno's hypothesis and Muller's paradox: sex chromosome dosage compensation may serve collective gene functions. BioEssays 34:930-933. Forsdyke DR, 2012

5.Wang J et al. (2016) Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X. Proc Natl Acad Sci USA doi/10.1073/pnas.1520113113 Wang J, 2016