Human Genetics Lecture 1 F2024 PDF

HUMAN GENETICS  INBORN ERROR CONCEPT (GARROD) The history of human biochemical genetics began when Sir Archibald Garrod initiated the brilliant studies of alkaptonuria. His lectures were documented in a monograph, Inborn Errors of Metabolism, which appeared in 1909 and in a modified form in 1923...

HUMAN GENETICS  INBORN ERROR CONCEPT (GARROD) The history of human biochemical genetics began when Sir Archibald Garrod initiated the brilliant studies of alkaptonuria. His lectures were documented in a monograph, Inborn Errors of Metabolism, which appeared in 1909 and in a modified form in 1923. With the reprinting of Garrod's Inborn Factors in Disease in 1989, there has been increasing recognition that his work provided one of the foundation stones of modern medical genetics. A biography describing the life and contributions of Garrod was published in 1993 Garrod had observed that patients with alkaptonuria excreted large quantities of homogentisic acid throughout their lifetimes, whereas other persons excreted none at all. The condition, he observed, had a familial distribution, one or more sibs were involved, and parents were normal. There was a high incidence of consanguineous marriages in the parents of his patients, as well as in the parents of similar patients studied elsewhere. Garrod consulted with a known geneticist named William Bateson, who explained that these observations can be explained if the defect was inherited as a recessive condition in terms of the recently rediscovered laws of Mendel. William Bateson Mendel's studies yielded three "laws" of inheritance: the law of dominance the law of segregation the law of independent assortment. Each of these can be understood through examining the process of meiosis. After his observations of patients with alkaptonuria, Garrod spotted similar phenomena in albinism, cystinuria, and pentosuria leading him to develop the following concept: that certain diseases of lifelong duration arise because an enzyme governing a single metabolic step is reduced in activity or missing altogether”. Garrod postulated that the accumulation of homogentisic acid in alkaptonuria indicates that this substance is a normal metabolite in the dissimilation of tyrosine. Remarkably, Garrod attributed its accumulation to a failure of the oxidation of homogentisic acid. 50 yrs later, Garrod's hypothesis was confirmed by the demonstration of a deficient activity of homogentisic acid oxidase in the liver of a patient with alkaptonuria (Seegmiller et al., 1958). ONE GENE-ONE ENZYME CONCEPT (BEADLE/TATUM) The term gene was first applied to the hereditary determinant of a unit characteristic by Wilhelm Johannsen in 1909. The one gene-one enzyme concept was developed by George Beadle and Edward Tatum (1941) from experiments using bread mold. Wilhelm Johannsen The one gene-one enzyme concept was well expressed by Tatum as follows: (1) All biochemical processes in all organisms are under genetic control. (2) These biochemical processes are resolvable into series of individual stepwise reactions. (3) Each biochemical reaction is under the ultimate control of a different single gene. (4) Mutation of a single gene results only in an alteration in the ability of the cell to carry out a single primary chemical reaction. The one gene-one enzyme concept had immediate explanatory potential for the inborn errors of metabolism that Garrod had described. “Inherited diseases such as alkaptonuria were produced by loss-of-function mutations in genes encoding enzymes Who linked DNA to heredity? For years, most scientists believed that protein, not DNA, was the carrier of hereditary information. This changed in 1944, when Oswald Avery performed a series of groundbreaking experiments with the bacteria that cause pneumonia. Oswald Avery (1877-1955) However, it was not until 1948 that the first enzyme defect in a human genetic disease was demonstrated by Quentin Gibson (1918-2011). This was the deficiency of cytochrome-b5 reductase in recessive methemoglobinemia. Quentin Gibson This was soon followed by the description : In 1952 by Cori and Cori of glucose 6-phosphatase deficiency in von Gierke disease (glycogen storage disease, type I) In 1953 by Jervis of phenylalanine hydroxylase deficiency in phenylketonuria (PKU). Metabolism of Phenylalanine. The cause of PKU is phenylalanine hydroxylase deficiency. The compounds which accumulate as a consequence of the block are shown.  GENETIC DIVERSITY IN HUMANS Garrod's chemical individuality and the concept of polymorphism Garrod recognized that the aberrant metabolism seen in a condition such as alkaptonuria might imply far more extensive chemical individuality, and he wrote: “… we are dealing with individualities of metabolism and not with the results of morbid processes …. these are merely extreme examples of variations of chemical behavior which are probably everywhere present in minor degrees and that just as no two individuals of a species are absolutely identical in bodily structure neither are their chemical processes carried out on exactly the same lines Garrod further said that "diathesis (predisposition to disease) is nothing else but chemical individuality" that he described as follows: “.... the factors which confer upon us our predispositions to and immunities from the various mishaps which are spoken of as diseases, are inherent in our very chemical structure; and even in the molecular groupings which confer upon us our individualities. Conclusion: Individuals have both molecular and biochemical individuality While physicians tend to regard the human population as a homogeneous group of "wild-type individuals" with an average that represents he normal value" for all determinants, to geneticists, this is an erroneous concept. The aggregate effect of our genes determines ho die of m oca dial infa c ion on a high-fat diet ho de elo cance on moking ho onl ca ie Meningococcus in the nasopharynx while another develops meningitis ho de elo o o e a i e thromboembolism ho i ce ible o alcoholi m. Garrod's concept of chemical individuality has found its explanation over the past three decades with the realization that the gene for a given protein frequently exists in different forms in different normal individuals” Example: ApoE2,ApoE3 and ApoE4  ApoE Isoforms The 3 alleles were termed ε2 (7% of pop), ε3 (79% of population) and ε4 (14% of population). The ε4 allele (genotypes E4/4 and E4/3) that is associated with higher low density lipoprotein cholesterol (LDL-C), considered atherogenic The ε2 allele (phenotypes E3/2 and E2/2) is associated with lower LDL-C levels and therefore has the opposite effect (anti-atherogenic) The E4 variant is the largest known genetic risk factor for late-onset sporadic Alzheimer's disease (AD) in a variety of ethnic groups. Caucasian (genotypes E4/4) have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles. At most genetic loci (such as the locus for the chain of hemoglobin), one standard allele accounts for the vast majority of the alleles in the population, and the alternate alleles are rare. At other genetic loci (such as the locus for the - chain of haptoglobin, a plasma protein), no single allele is sufficiently common to be designated as standard or normal. A polymorphic locus (or nucleotide site) is one at which the most common allele has a frequency of less than 0.99 By definition, when a polymorphism exists at a genetic locus, at least 2 percent of the population must be heterozygous at that locus. Note that this definition is concerned only with the frequency of variants at a locus and not with the functional consequences of the variant. Attention was focused on DNA polymorphism by the discovery of RFLPs (restriction fragment length polymorphism) as well as CNVs (copy number variations). Approximately 1 in 100 to 1 in 200 base pairs in the human genome is polymorphic A site is defined as polymorphic when at least 1 percent of the chromosomes have a sequence different from that of the majority. The term allele is now often extended to describe any nucleotide variation, such as DNA fragment size differences detected as RFLPs, even when not associated with an expressed gene locus. With the recognition of the extensive amount of polymorphism in DNA (millions of nucleotide differences between two random haploid genomes), including variation in non-expressed sequences, it becomes obvious that most DNA polymorphism is not associated with phenotypic effects. A modest fraction of genomic polymorphism is associated with effects on the phenotype that account for variations such as ethnic differences and human individuality without a significant effect on health or disease. Another portion of the polymorphism would be associated with phenotypic variation that might have relatively subtle and complex effects on susceptibility to disease. These variations would include genes affecting susceptibility to hypertension, atherosclerosis, malignancy, psychiatric illness, and infection. (Example, ApoE gene)  THE RECOMBINANT DNA REVOLUTION Recombinant DNA methodology has transformed the study of human genetics. The changes trace their roots back to the description of the structure of DNA by Watson and Crick in 1953 By the 1970s, restriction enzymes were described, and their value for preparing restriction maps was recognized. The basic procedures for cloning DNA fragments in plasmid and bacteriophage vectors were described, opening the recombinant DNA era Methods for DNA sequencing as well as the existence of introns and exons within genes were described. Southern blotting and northern blotting became routine, and the polymerase chain reaction (PCR) brought another leap forward.