Efforts to make and apply humanized yeast

Abstract

Despite a billion years of divergent evolution, the baker's yeast Saccharomyces cerevisiae has long proven to be an invaluable model organism for studying human biology. Given its tractability and ease of genetic manipulation, along with extensive genetic conservation with humans, it is perhaps no surprise that researchers have been able to expand its utility by expressing human proteins in yeast, or by humanizing specific yeast amino acids, proteins or even entire pathways. These methods are increasingly being scaled in throughput, further enabling the detailed investigation of human biology and disease-specific variations of human genes in a simplified model organism.

Keywords: evolution; functional genomics; high-throughput assays; humanization; yeast.

Figure 1

Humans and yeast share thousands of orthologous genes. The Venn diagram illustrates counts of human–yeast orthologs [2], grouped according to the nature of the orthology (classifying orthologs according to whether their count in humans:yeast is 1:1, many:1, or many:many) and whether the yeast genes are essential or not under standard laboratory growth conditions [3]. (A colour version of this figure is available online at: http://bfg.oxfordjournals.org)

Figure 2

Five degrees of yeast humanization. Yeast have proven useful for the direct study of human biology in a variety of forms, illustrated here to distinguish those cases in which yeast were simply studied for human-specific processes and drugs (degree 0), to the heterologous expression of human genes in yeast (degree 1), all the way to the directed replacement of specific amino acids, genes, and pathways (degrees 2–4, respectively). (A colour version of this figure is available online at: http://bfg.oxfordjournals.org)

Figure 3

Three examples of humanized yeast, relevant to neurodegenerative disorders, metabolic disorders and cholesterol biosynthesis. (A) (Left) Yeast show diffuse distribution of α-synuclein during moderate expression (NoTox), aggregation during overexpression (HiTox) and rescue of aggregation by administration of an N-aryl benzimidazole (NAB). (Right) Degeneration (white arrowheads) of C. elegans DA neurons during overexpression of α-synuclein (top) and protection by NAB administration (bottom). Figures are adapted from Tardiff et al. [30] with permission. (B) (top) Growth over time of Δcys4 yeast expressing the major human allele of cystathione-β-synthase (CBS) as a function of varying concentrations of vitamin B6. (bottom) Growth rate at various levels of vitamin B6 for several minor human alleles, relative to the major human allele. Figures are adapted from Mayfield et al. [31] with permission. (C) Seventeen of 19 tested genes of the yeast sterol biosynthesis pathway are replaceable by their human equivalents. Figure adapted from Kachroo et al. [6] with permission. (A colour version of this figure is available online at: http://bfg.oxfordjournals.org)