Calculating the rate of evolution in terms of nucleotide substitutions seems to give a value so high that many of the mutations involved must be neutral ones.

Evolutionary Rate at the Molecular Level

Autophagy is a highly conserved catabolic process induced under various conditions of cellular stress, which prevents cell damage and promotes survival in the event of energy or nutrient shortage and responds to various cytotoxic insults. Thus, autophagy has primarily cytoprotective functions and needs to be tightly regulated to respond correctly to the different stimuli that cells experience, thereby conferring adaptation to the ever-changing environment. It is now apparent that autophagy is deregulated in the context of various human pathologies, including cancer and neurodegeneration, and its modulation has considerable potential as a therapeutic approach.

Mechanism and medical implications of mammalian autophagy

Alzheimer mechanisms and therapeutic strategies.

Methodes d'extraction d'enzymes, d'electrophorese en gel et de coloration specifique des enzymes utilisees pour etudier la variation genetique chez Escherichia coli et d'autres bacteries. Les procedures decrites peuvent s'appliquer, avec quelques modifications mineures, a toute espece de bacterie

Methods of multilocus enzyme electrophoresis for bacterial population genetics and systematics

Genetic mapping provides a powerful approach to identify genes and biological processes underlying any trait influenced by inheritance, including human diseases We discuss the intellectual foundations of genetic mapping of Mendelian and complex traits in humans, examine lessons emerging from linkage analysis of Mendelian diseases and genome-wide association studies of common diseases, and discuss questions and challenges that lie ahead

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Genetic Mapping in Human Disease

There are a large number of different enzymes synthesized in the human organism, and many of these probably contain more than one structurally distinct polypeptide chain. If current theories about genes and proteins are correct we must suppose that the primary structure of each of these different polypeptides is determined by a separate gene locus, and that there are probably also other loci which are specifically concerned with regulating the rate of synthesis of particular polypeptides or groups of polypeptides. Furthermore, we may expect that genetical diversity in a human population will to a considerable extent be reflected in enzymic diversity. That is to say, in differences between individuals either in the qualitative characteristics of the enzymes they synthesize, or in differences in rates of synthesis. The work I am going to discuss was largely aimed at trying to get some idea of the extent and character of such genetically determined enzyme diversity among what may be regarded as normal individuals. When my colleagues and I started on this line of work about three years ago the information available about this aspect of the subject was very limited. It had of course been recognized for quite a long time that there are many rare metabolic disorders, the so-called 'inborn errors of metabolism', which are due to genetically determined deficiencies of specific enzymes (Harris I963). These conditions can in general be attributed to mutant genes which result either in the synthesis of an abnormal enzyme protein with defective catalytic properties, or in a gross reduction in rate of synthesis of a specific enzyme protein. By and large such genes appear to be relatively uncommon and have frequencies of between 0.01 and 0-001 in the general population. Heterozygotes often show a partial enzyme deficiency though they are usually in other respects quite healthy. A few cases are also known where a specific enzyme deficiency occurs quite commonly in certain populations. The most extensively studied example of this is glucose 6-phosphate dehydrogenase deficiency, and it seems likely that in this particular case the relatively high incidence in certain populations is attributable to a specific selective advantage which the deficiency may confer in situations where endemic malaria is an important selective agent (Motulsky 1964). Virtually all these enzyme deficiencies have been identified in the first instance because of some more or less striking clinical or metabolic disturbance of which they were the cause. They therefore represent a highly selected group of mutants,

Enzyme polymorphisms in man

Defects in autophagy—a process that enables the degradation of unwanted or damaged intracellular proteins and organelles—are associated with the accumulation of aggregate-prone proteins. Defects in neuronal autophagy may have a role in neurodegenerative disease that are associated with aberrant protein accumulation, such as Alzheimer disease and Parkinson disease. Rubinsztein and Harris discuss how defects in autophagic pathways might cause these diseases and highlight how autophagy-modulating drugs might be used as therapy.

Harry Harris

Papers

Enzyme polymorphisms in man

Control of autophagy as a therapy for neurodegenerative disease