Analysis of phenotype-genotype connection: the story of dissecting disease pathogenesis in genomic era in China, and beyond

Abstract

DNA is the ultimate depository of biological complexity. Thus, in order to understand life and gain insights into disease pathogenesis, genetic information embedded in the sequence of DNA base pairs comprising chromosomes should be deciphered. The stories of investigating the association between phenotype and genotype in China and other countries further demonstrate that genomics can serve as a probe for disease biology. We now know that in Mendelian disorders, one gene is not only a dictator of one phenotype but also a dictator of two or more distinct disorders. Dissecting genetic abnormalities of complex diseases, including diabetes, hypertension, mental diseases, coronary heart disease and cancer, may unravel the complicated networks and crosstalks, and help to simplify the complexity of the disease. The transcriptome and proteomic analysis for medicine not only deepen our understanding of disease pathogenesis, but also provide novel diagnostic and therapeutic strategies. Taken together, genomic research offers a new opportunity for determining how diseases occur, by taking advantage of experiments of nature and a growing array of sophisticated research tools to identify the molecular abnormalities underlying disease processes. We should be ready for the advent of genomic medicine, and put the genome into the doctors' bag, so that we can help patients to conquer diseases.

Figure 1

Minorities in China (from website: http://www.chinaculture.org/gb/cn_zggk/2004-06/28/content_55993.htm).

Figure 2

Brachydactyly type A-1 and IHH mutation. (a) Short middle phalanges (i) and relevant radiographs (ii). (b) Structure of IHH and location of mutations. (c) Schematic of IHH protein and sites of amino acid residue transition and cleavage. Reproduced with permission from Gao et al. (2001) Nat. Genet. © Macmillan Magazines Ltd.

Figure 3

(a) Dentinogenesis imperfecta 1, (b) hearing loss and (c) mutations in DSPP. Figure (a) was reproduced with permission from Zhang et al. (2001) Nat. Genet.; figure (b) was reproduced with permission from Xiao et al. (2001) Nat. Genet.; figure (c) was modified with permission from Xiao et al. (2001) Nat. Genet. © Macmillan Magazines Ltd.

Figure 4

One connexin, two diseases. (a) Predicted arrangement of the connexin 31 molecule within the cell membrane. Four transmembrane domains (M1–M4) separate the intracellular N-terminal domain (N), the two extracellular loops (E1 and E2), the cytoplasmic loop (CL) and the C-terminal domain. The locations of mutations causing hearing loss are shown by green spots, while mutations associated with the EKV are indicated by red spots. (b) Audiogram of patients with high-frequency hearing loss. (c) Clinical features of EKV. Figure (a) was reproduced with permission from Steel (1998) Nat. Genet.; figure (b) was reproduced with permission from Xia et al. (1998) Nat. Genet.; figure (c) was reproduced with permission from Richard et al. (1998) Nat. Genet. © Macmillan Magazines Ltd.

Figure 5

Age-standardized mortality for the five leading causes of death (a) among study participants who were rural or urban residents and (b) from malignant neoplasms.

Figure 6

Schematic of feature and molecular pathogenesis of AML M2 with t(8;21). (a) Morphology of AML M2 cells. (b) Mutations in C-KIT oncoprotein reported by SIH (Wang et al. 2005). Letters in black represent mutations reported previously, whereas those in red represent mutations first identified in their works. (c) Model for disease pathogenesis of t(8;21) AML.