The Path to Conserved Extended Haplotypes: Megabase-Length Haplotypes at High Population Frequency

This minireview describes the history of the conceptual development of conserved extended haplotypes (CEHs): megabase-length haplotypes that exist at high (≥0.5%) population frequency. My career began in internal medicine, shifted to pediatrics, and clinical practice changed to research. My research interest was initially in hematology: on plasma proteins, their metabolism, synthesis, and function. This narrowed to a focus on proteins of the human complement system, their role in immunity and their genetics, beginning with polymorphism and deficiency of C3. My group identified genetic polymorphisms and/or inherited deficiencies of C2, C4, C6, and C8. After defining glycine-rich beta glycoprotein as factor B (Bf) in the properdin system, we found that the genes for Bf (CFB), C2, C4A, and C4B were inherited as a single haplotypic unit which we named the “complotype.” Complotypes are located within the major histocompatibility complex (MHC) between HLA-B and HLA-DRB1 and are designated (in arbitrary order) by their CFB, C2, C4A, and C4B types. Pedigree analysis revealed long stretches (several megabases) of apparently fixed DNA within the MHC that we referred to as “extended haplotypes” (later as “CEHs”). About 10 to 12 common CEHs constitute at least 25 – 30% of MHC haplotypes among European Caucasian populations. These CEHs contain virtually all the most common markers of MHC-associated diseases. In the case of type 1 diabetes, we have proposed a purely genetic and epigenetic model (with a small number of Mendelian recessive disease genes) that explains all the puzzling features of the disease, including its rising incidence.

Genetic susceptibility to multiple sclerosis: interactions between conserved extended haplotypes of the MHC and other susceptibility regions

Background To study the accumulation of MS-risk resulting from different combinations of MS-associated conserved-extended-haplotypes (CEHs) of the MHC and three non-MHC “risk-haplotypes” nearby genes EOMES, ZFP36L1, and CLEC16A. Many haplotypes are MS-associated despite having population-frequencies exceeding the percentage of genetically-susceptible individuals. The basis of this frequency-disparity requires explanation. Methods The SNP-data from the WTCCC was phased at the MHC and three non-MHC susceptibility-regions. CEHs at the MHC were classified into five haplotype-groups: (HLA-DRB1*15:01 ~ DQB1*06:02 ~ a1)-containing (H +); extended-risk (ER); all-protective (AP); neutral (0); and the single-CEH (c1). MS-associations for different “risk-combinations” at the MHC and other non-MHC “risk-loci” and the appropriateness of additive and multiplicative risk-accumulation models were assessed. Results Different combinations of “risk-haplotypes” produce a final MS-risk closer to additive rather than multiplicative risk-models but neither model was consistent. Thus, (H +)-haplotypes had greater impact when combined with (0)-haplotypes than with (H +)-haplotypes, whereas, (H +)-haplotypes had greater impact when combined with a (c1)-haplotypes than with (0)-haplotypes. Similarly, risk-genotypes (0,H +), (c1,H +), (H + ,H +) and (0,c1) were additive with risks from non-MHC risk-loci, whereas risk-genotypes (ER,H +) and (AP,c1) were unaffected. Conclusions Genetic-susceptibility to MS is essential for MS to develop but actually developing MS depends heavily upon both an individual’s particular combination of “risk-haplotypes” and how these loci interact.

Genetic Adaptation in New York City Rats

Brown rats (Rattus norvegicus) thrive in urban environments by navigating the anthropocentric environment and taking advantage of human resources and by-products. From the human perspective, rats are a chronic problem that causes billions of dollars in damage to agriculture, health and infrastructure. Did genetic adaptation play a role in the spread of rats in cities? To approach this question, we collected whole-genome sequences from 29 brown rats from New York City (NYC) and scanned for genetic signatures of adaptation. We tested for (i) high-frequency, extended haplotypes that could indicate selective sweeps and (ii) loci of extreme genetic differentiation between the NYC sample and a sample from the presumed ancestral range of brown rats in northeast China. We found candidate selective sweeps near or inside genes associated with metabolism, diet, the nervous system and locomotory behavior. Patterns of differentiation between NYC and Chinese rats at putative sweep loci suggest that many sweeps began after the split from the ancestral population. Together, our results suggest several hypotheses on adaptation in rats living in close proximity to humans.

Genetic Susceptibility to Multiple Sclerosis: Interactions between Conserved Extended Haplotypes of the MHC and other Susceptibility Regions

BACKGROUNDTo study the accumulation of MS-risk resulting from different combinations of MS-associated conserved-extended-haplotypes (CEHs) of the MHC and three non-MHC “risk-haplotypes” nearby genes EOMES, ZFP36L1, and CLEC16A. Many haplotypes are MS-associated despite having population-frequencies exceeding the percentage of genetically-susceptible individuals. The basis of this frequency-disparity requires explanation. MEHTODSWTCCC SNP-data was phased at the MHC and three non-MHC susceptibility-regions. CEHs at the MHC were classified into five haplotype-groups: (HLA-DRB1*15:01~DQB1*06:02~a1)-containing (H+); extended-risk (ER); all-protective (AP); neutral (0); and the single-CEH (c1). MS-associations for different “risk-combinations” at the MHC and other non-MHC “risk-loci” and the appropriateness of additive and multiplicative risk-accumulation models were assessed.RESULTSDifferent combinations of “risk-haplotypes” produce a final MS-risk closer to additive rather than multiplicative risk-models but neither model was consistent. Thus, (H+)-haplotypes had greater impact when combined with (0)-haplotypes than with (H+)-haplotypes, whereas, (H+)-haplotypes had greater impact when combined with a (c1)-haplotypes than with (0)-haplotypes. Similarly, risk-genotypes (0,H+), (c1,H+), (H+,H+) and (0,c1) were additive with risks from non-MHC risk-loci, whereas risk-genotypes (ER,H+) and (AP,c1) were unaffected.CONCLUSIONSGenetic-susceptibility to MS is essential for MS to develop but actually developing MS depends heavily upon both an individual’s particular combination of “risk-haplotypes” and how these loci interact.

Genetic Adaptation in New York City Rats

Brown rats (Rattus norvegicus) thrive in urban environments by navigating the anthropocentric environment and taking advantage of human resources and by-products. From the human perspective, rats are a chronic problem that causes billions of dollars in damage to agriculture, health and infrastructure. Did genetic adaptation play a role in the spread of rats in cities? To approach this question, we collected whole-genome sequences from 29 brown rats from New York City (NYC) and scanned for genetic signatures of adaptation. We tested for (i) high-frequency, extended haplotypes that could indicate selective sweeps and (ii) loci of extreme genetic differentiation between the NYC sample and a sample from the presumed ancestral range of brown rats in northeast China. We found candidate selective sweeps near or inside genes associated with metabolism, diet, the nervous system and locomotory behavior. Patterns of differentiation between NYC and Chinese rats at putative sweep loci suggests that many sweeps began after the split from the ancestral population. Together, our results suggest several hypotheses on adaptation in rats living in close proximity to humans.

Genetic Susceptibility to Multiple Sclerosis: Interactions between Conserved Extended Haplotypes of the MHC and other Susceptibility Regions

OBJECTIVETo study the accumulation of MS-risk resulting from different combinations of MS-associated conserved-extended-haplotypes of the MHC and three non-MHC risk-loci nearby genes EOMES, ZFP36L1, CLEC16A.BACKGROUNDDefining “genetic-susceptibility” as having a non-zero probability of developing MS, both theoretical considerations and epidemiological observations indicate that only 2.2–4.5% of northern-populations can possibly be “genetically-susceptible” to MS. Nevertheless, many haplotypes (both within the MHC and elsewhere) are unequivocally MS-associated and, yet, have population-frequencies of >20%. Such frequency-disparities underscore the complex-interactions that must occur between these “risk-haplotypes” and MS-susceptibility.DESIGN/MEHTODSThe WTCCC dataset was statistically-phased at the MHC and at three other susceptibility-regions. Haplotypes were stratified by their impact on “MS-risk”. MS-associations for different combinations of “risk-haplotypes” were assessed. The appropriateness of both additive and multiplicative risk-accumulation models was determined.RESULTSCombinations of different “risk-haplotypes” produced an MS-risk that was considerably closer to an additive model than a multiplicative model. Nevertheless, neither of these simple probability-models adequately accounted for the accumulation of disease-risk in MS at these four loci.CONCLUSIONS“Genetic-susceptibility” to MS seems to depend upon the exact state at each “risk-locus” and upon specific gene-gene combinations across loci. Moreover, “genetic-susceptibility” is both rare in the population and, yet, is a necessary condition for MS to develop in any individual. In this sense, MS is a “genetic” disease. Nevertheless although, “genetic-susceptibility” is a necessary condition for MS to develop, environmental factors (whatever these may be) and stochastic processes are also necessary determinants of whether a “genetically-susceptible” individual will actually get MS.Author SummaryDefining a “genetically-susceptible” individual to be any person in the population who has any chance of developing multiple sclerosis (MS), we demonstrate that, at a theoretical level and using widely-accepted epidemiological observations, only 2.2-4.5% of individuals in northern populations can possibly be “genetically susceptible” to MS. Thus, more than 95.5% of individuals in these populations have no chance of getting MS, regardless of the environmental circumstances that they may experience.Nevertheless, certain “susceptibility-haplotypes” (e.g., HLA-DRB1*15:01~DQB1*06:02) have a far greater carrier-frequency than 2.2-4.5%. Consequently, most carriers of these “susceptibility-haplotypes” have no chance of getting MS and, therefore, their “susceptibility” must arise from some combination of these haplotypes with other “susceptibility-haplotypes”. By analyzing such combinatorial impacts at four susceptibility-loci, we found significant interactions both within and between the different “susceptibility-haplotypes”, thereby confirming the relationship between “genetic-susceptibility” and specific gene-gene combinations.The nature of “genetic-susceptibility” developed here is applicable to other complex genetic disorders. Indeed, any disease for which the MZ-twin concordance rate is substantially greater than the life-time risk in the general population, only a small fraction of the population can possibly be in the “genetically-susceptible” subset (i.e., have any chance of developing the disease).