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MutatioMutationn

Dan GraurDan Graur

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From an evolutionary viewpoint, a mutation is a DNA sequence in the germline that differs from its counterparts in somatic cells, and which is passed on from parents to progeny, thereby endowing an individual in the next generation with a novel genetic constitution. Mutations are the ultimate source of variation and novelty in evolution.

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Mutations: Classification Schemes

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The Mutational “Balancing Act”

Too many mutations No LifeToo few mutations No Evolution

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MutationsMutations can occur in can occur in either either somaticsomatic or or germlinegermline cells. cells.

Somatic mutations are Somatic mutations are notnot inherited in inherited in animalsanimals..

They are, therefore, They are, therefore, evolutionarily evolutionarily irrelevantirrelevant. .

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Vascular plantsVascular plants do not have a do not have a sequestered sequestered germlinegermline and, and, therefore, the therefore, the distinction distinction between between somaticsomatic and and germlinegermline mutations is not mutations is not absolute.absolute.

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Replication-dependent mutationsReplication-independent mutations

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DNA sequences are DNA sequences are usually copied exactly usually copied exactly during DNA during DNA replication. replication.

Rarely, however, Rarely, however, errors occur, giving errors occur, giving rise to novel rise to novel sequences. sequences. These These errors are called errors are called replication-dependent replication-dependent mutations. mutations.

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Mutations may be divided Mutations may be divided into into induced induced and and spontaneousspontaneous mutations mutations according to whether or not according to whether or not the mutation was caused by the mutation was caused by an an external mutagenexternal mutagen, such , such as as caffeinecaffeine, nitrous acid, , nitrous acid, ethidium bromide, or ethidium bromide, or ionizing and ultraviolet ionizing and ultraviolet radiation.radiation.

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Chernobyl

Examples of mutagens:Examples of mutagens:

Hiroshima

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Mutations affect the genotype.

Mutations may or may not affect the phenotype.

A strict unambiguous correspondence between genotype and phenotype does not exist.

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Mutations that affect the Mutations that affect the phenotype may be:phenotype may be: amorphic amorphic (loss of (loss of function), function), hypomorphichypomorphic (partial loss of function), (partial loss of function), hypermorphichypermorphic (increase in (increase in function), function), neomorphicneomorphic (gain (gain of function)… of function)…

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An amorphic mutation in tyrosinase and its consequences.

NAIROBI, Kenya — The belief that albino body parts have magical powers has driven thousands of Africa's albinos into hiding, fearful of losing their lives to dealers who can sell their limbs for as much as $75,000.

MLLAVLYCLLWSFQTSAGHFPRACVSSKNLMEKECCPPWSGDRSPCGQLSGRGSCQNILLSNAPLGPQFPFTGVDDRESWPSVFYNRTCQCSGNFMGFNCGNCKFGFWGPNCTERRLLVRRNIFDLSAPEKDKFFAYLTLAKHTISSDYVIPIGTYGQMKNGSTPMFNDINIYDLFVWMHYYVSMDALLGGSEIWRDIDFAHEAPAFLPWHRLFLLRWEQEIQKLTGDENFTIPYWDWRDAEKCDICTDEYMGGQHPTNPNLLSPASFFSSWQIVCSRLEEYNSHQSLCNGTPEGPLRRNPGNHDKSRTPRLPSSADVEFCLSLTQYESGSMDKAANFSFRNTLEGFASPLTGIADASQSSMHNALHIYMNGTMSQVQGSANDPIFLLHHAFVDSIFEQWLRRHRPLQEVYPEANAPIGHNRESYMVPFIPLYRNGDFFISSKDLGYDYSYLQDSDPDSFQDYIKSYLEQASRIWSWLLGAAMVGAVLTALLAGLVSLLCRHKRKQLPEEKQPLLMEKEDYHSLYQSHL

Pro81Leu

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 Acquisition of a new transcription factor binding site

The sequence 5'-TAATAA-3’ changed into 5'-TGATAA-3’, creating a new binding site. 

A neomorphic mutation in a nongenic region between the -globin genes and their upstream regulatory elements causes -thalassemia

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Mutations

Substitution

Segmental Inversion

Recombination

Substantive

Contextual

Deletion

Insertion

Point

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transition

transversion

recombination

deletion

insertion

inversion

substitutions

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synonymoussynonymous

nonsynonymousnonsynonymous

nonsensenonsense

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Codons that can mutate to a termination codon by a single nucleotide substitution, e.g., UGC (Tyr), are called ppreterminationretermination codons.

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Mutations in stop codons causing the translation to continue are called “sense” mutations.

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Each sense codon can mutate to nine other codons by means of a single nucleotide substitution.

Example: CCU (Pro) can experience six nonsynonymous substitutions, to UCU (Ser), ACU (Thr), GCU (Ala), CUU (Leu), CAU (His), or CGU (Arg), and three synonymous substitutions, to CCC, CCA, or CCG.

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Since the standard genetic code consists of 61 sense codons, there are:

61 9 = 549 possible nucleotide substitutions.

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Relative frequencies of different types of mutational

substitutions in a random protein-coding sequence

⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐

Substitution Number Percent⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐

T otal in al l codons 549 100Synonymous 134 25Nonsynonymous 415 75

Missense 392 71Nonsense 23 4

T otal in fi rst codon 183 100Synonymous 8 4Nonsynonymous 175 96

Missense 166 91Nonsense 9 5

T otal in seco ndcodon 183 100Synonymous 0 0Nonsynonymous 183 100

Missense 176 96Nonsense 7 4

T otal in thir dcodon 183 100Synonymous 126 69Nonsynonymous 57 31

Missense 50 27Nonsense 7 4

⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐⏐

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RecombinationRecombination

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reciprocal

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non-reciprocal

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Reciprocal recombination is a powerful generator of variability. For example, recombinations between 5’—AACT—3’ and 5’—CTTG—3’ may result in 6 novel6 novel sequences:

5’—ATTG—3’5’—CACT—3’ 5’—AATG—3’5’—CTCT—3’5’—AACG—3’5’—CTTT—3’

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The more variants there are, the more variants will come into being through recombination, and the rate of generating new genetic variation will become quite high.

“Variation begets variation.” Golding and Strobeck (1983)

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Insertion & DeletionInsertion & Deletion

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Unequal Crossing OverUnequal Crossing Over

Insertion

Insertion

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IntrastrandIntrastrandDeletionDeletion

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When two sequences are compared, it is impossible to tell whether a deletion has occurred in one or an insertion has occurred in the other.

INsertions and DELetions are collectively referred to as INDELs.

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The number of nucleotides in an indel range from one or a few nucleotides to contiguous stretches of thousands of nucleotides.

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Indel lengths exhibit a bimodal frequency distribution, with short indels (up to 20–30 nucleotides) being caused by errors of DNA replication, such as slipped-strand mispairing, and with long indels occurring mainly because of unequal crossing-over, site-specific recombination, DNA transposition, or horizontal gene transfer.

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InversionInversion

(a) chromosome breakage and rejoining(b) intrachromosomal crossing-over between two homologous segments that are oriented in opposite directions

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Spatial Spatial DistributiDistributi

on on of of

MutationsMutations

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Mutations do not occur randomly throughout the genome. Some regions are hotspots of mutation.

One such hotspot is the dinucleotide 5'CG3' (CpG), in which the cytosine is frequently methylated in many animal genomes, and may mutate to 5'TG3'.

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Mutations do not occur randomly throughout the genome. Some regions are hotspots of mutation.

The dinucleotide 5'TT3' is a hotspot of mutation in many prokaryotes, but not in eukaryotes.

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PalindromesPalindromes

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Molecular palindromeMolecular palindrome

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Fluctuation test. Salvadore Luria and Max Delbrück. 1943.

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Replica plating. Ester and Joshua Lederberg. 1952.

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A mutation is expected to occur with the same frequency under conditions in which it confers an advantage on the organism carrying it, as under conditions in which it confers no advantage or is deleterious.

“It may seem a deplorable imperfection of nature that mutability is not restricted to changes that enhance the adeptness of their carriers.”

Theodosius Dobzhansky (1970)