2 gene function

7/29/2019 2 Gene Function

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THE BEGINNINGS OF MOLECULARGENETICS: GENE FUNCTION

Discuss from a historical perspectivethe discoveries that led to thehypothesis that one gene defines one

polypeptide List and describe several genetic

defects leading to enzyme deficienciesin humans

Explain how genes determine thestructure of proteins and the effects ofmutations that alter a proteins structure


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GENE CONTROL OF ENZYMESTRUCTURE

Garrods Hypothesis of Inborn Errors of

Metabolism

One Gene-One Enzyme Hypothesis Alkaptonuria

Phenylketonuria

Albinism

Lesch-Nyhan Syndrome

Tay-Sachs Disease


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GENE CONTROL OF PROTEINSTRUCTURE

Sickle-Cell Anemia

Cystic Fibrosis


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Garrods Hypothesis of Inborn

Errors of Metabolism English physician Archibald Garrod

Provided the first evidence (1902) thatgenes were related to enzymes with his

studies on patients with alkaptonuria From his observations, Garrod

concluded that alkaptonuria is a geneticdisease caused by the absence of a

particular enzyme necessary for themetabolism of homogentisic acid

Since the mutation was recessive, only

homozygotes express the defect


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One Gene-One Enzyme Hypothesis George Beadle and Edward Tatum (1942)

showed in their studies with the fungusNeurospora crassa that there was a

direct relationship between genes andenzymes

Beginning of Biochemical Genetics

They proposed the one gene-oneenzyme hypothesis, which states that aspecific gene controls the production ofa single active enzyme


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Life cycle ofthe haploid,mycelial-form fungus

Neurosporacrassa


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Method devised byBeadle and Tatum toisolate auxotrophicmutations in

Neurospora


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Methionine biosynthetic pathway showing fourgenes in Neurospora crassathat code for the

enzymes that catalyze each reaction


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One Gene-One Enzyme Hypothesis

Mutations that result in the loss of theenzyme activity lead to the accumulationof precursors in a metabolic pathwayand an absence of end product

Enzymes are proteins that can consist ofmore than one polypeptide, and genesencode individual polypeptide chains

The modern description of thishypothesis then is: one gene-onepolypeptide


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Phenylalanine-tyrosine metabolic pathways


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Inborn errors ofmetabolism inbreakdown of

phenylalanineand tyrosine


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Phenylketonuria Phenylketonuria (PKU) is caused by an

autosomal recessive mutation in the

gene encoding the enzyme

phenylalanine hydroxylase that occurs

in about 1 of every 12,000 Caucasianbirths


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Phenylketonuria

Without this enzyme, phenylalanine (anessential amino acid) is converted tophenylpyruvic acid, which affects cells of

the central nervous system causingmental retardation, slow growth, and earlydeath

A person with PKU can live normally ifphenylalanine is restricted from the diet


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Albinism Albinism is caused by an autosomal recessive

mutation in a gene coding an enzyme(tyrosinase) that converts tyrosine to the brown

pigment melanin1:33,000 Caucasians- 1:28,000 African American

Without melanin, albinos have white skin andhair, and red eyes

They are more sensitive to light becausemelanin plays a role in protecting the skinagainst UV light from the sun


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Red eyes and white skin and hair in an albino


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Albinism

At least two different mutations areknown that occur in different steps of themelanin pathway

Thus if two albinos have children, the

children can be normal if the mutationscomplement


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Lesch-Nyhan Syndrome Lesch-Nyhan Syndrome is caused by a

recessive mutation in the gene encodinghypoxanthine guanine phosphoribosyl

transferase (HGPRT), a gene on the Xchromosome

1:10,000 males are affected

HGPRT is involved in a purine utilizationpathway


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Lesch-Nyhan Syndrome

When it is absent, excess purine basesaccumulate and are converted to uricacid which builds up in the body

Feeding disorder, mental retardationand self-mutilation are characteristic ofthis disease, and it results in prematuredeath (before the age of 20)

A f l


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A case of mentalretardation due toLesch-Nyhan

Syndrome


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Tay-Sachs Disease Tay-Sachs Disease is a lysosomal-

storage disease that is caused by arecessive mutation in the gene encoding

the enzyme N-acetylhexoaminidase A It is rare in the population at large but

high in Ashkenazi Jews

N-acetylhexoaminidase A cleaves aterminal N-acetylhexoaminidase groupof a brain ganglioside


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Tay-Sachs Disease

Without the enzyme, unprocessedgangliosides accumulate in brain cells,leading to cerebral degeneration and

death by age 3

There is rapid neurological degeneration

associated with this disease that leads togeneralized paralysis, blindness, loss ofhearing, and premature death


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The biochemical step for the conversion of the brainganglioside GM2 to the ganglioside GM3, catalyzed bythe enzyme N-acetylhexosaminidase A (hex A)


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A child with Tay-Sachs

Accumulation ofgangliosides inthe brain cells


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GENE CONTROL OF

PROTEINSTRUCTURE


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Sickle-Cell Anemia: Symptomsand Causes

Sickle-cell anemia is the result of amutation in a gene encoding the polypeptide subunit of hemoglobin

In the polypeptide chain, the aminoacid glutamic acid is replaced by

valine, a substitution that is caused bya point mutation in the gene


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The hemoglobinmolecule


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Sickle-Cell Anemia: Symptomsand Causes

This autosomal co-dominant mutationcauses a single amino acid substitutionin the chain which alters the chemical

structure of hemoglobin inside of redblood cells and changes the oxygencarrying capabilities of the molecule

Red blood cells carrying the mutanthemoglobin are sickle-cell shaped, morefragile than normal cells and not as

flexible


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The first seven N-terminal amino acids in normal andsickled hemoglobin polypeptides


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Electrophoresis

of hemoglobin

variants


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Other Hemoglobin Mutants

Over two-hundred hemoglobin mutants

in the or chains have beendetected, and several are well

characterized

E l f i id b tit ti f d i


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Examples of amino acid substitutions found in polypeptides of various human hemoglobin variants

E l f i id b tit ti f d i


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Examples of amino acid substitutions found in polypeptides of various human hemoglobin variants


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Cystic Fibrosis Cystic Fibrosis (CF) is caused by an autosomal

recessive mutation in a gene that encodes theCF protein

1:2,000 Caucasians, 1:23 heterozygous carrier

(most common lethal autosomal recessive) -1:90,000 Asians

The defective gene was initially identified byRFLP mapping on chromosome 7 rather than

biochemical testing Normal Cystic Fibrosis Transmembrane

Conductance Regulator (CFTR) is a chloridechannel in some types of cell membranes

Proposed structure for cystic fibrosis


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Proposed structure for cystic fibrosistransmembrane conductance regulator (CFTR)


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Cystic Fibrosis

In people with CF, the mutated geneencodes an abnormal CFTR protein,which causes abnormal salt transport

across membranes

This leads to the accumulation of mucusin the lungs and pancreas and other

symptoms Lethal disease: Life expectancy about 40

yrs of age


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THE END

2 gene function

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