wallis - genetic descriptors

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Genetic Descriptors and

Disorders

Gillian Wallis ([email protected])

Introduction to Genetics


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Outline Genes and the Human Genome

Human Genome Sequence Variation What is a genetic disease?

Patterns of inheritance


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Genes and the human genome


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Human Genome

Most human cellscontain 46 chromosomes:

2 sex chromosomes(X,Y):

XYin males.

XX in females.

22 pairs of chromosomesnamed autosomes.


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Genes are distributed along thechromosome interspersed by non-coding

DNA. Locuslocation of agene/markeron thechromosome.

Alleleone variant form of a

gene/marker at a particular locus.

Locus1

Possible Alleles: A1,A2

Locus2

Possible Alleles: B1,B2,B3


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Genotype:

Genetic makeup all the genetic information receivedfrom the mother and father

Phenotype:

Observable characteristics, what can be measured orobserved eg disease status, blood pressure, weight

Depends on genotype and environment

Genotypes Phenotypes


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The haploid human genome

23 chromosomes (diploid: 46XX or 46XY)

3,200,000,000 base pairs of DNA

30,000 genes (?)


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Begun formally in 1990, the U.S. Human Genome

Project was a 13-year effort coordinated by the U.S.

Department of Energy and the National Institutes of

Health.

The project originally was planned to last 15 years, but

rapid technological advances accelerated the

completion date to 2003.

Human Genome Project


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identify all the approximate 30,000 genes in human DNA

determine the sequences of the 3 billion chemical base pairs

that make up human DNA

store this information in databasesimprove tools for data analysis

transfer related technologies to the private sector

address the ethical, legal, and social issues (ELSI) that may

arise from the project.

Human Genome Project: Goals


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Whose genome was sequenced?

The sequence is composed of the D

of an estimated 10 to 20 anonymous

individuals across different racial and

ethnic groups.

The human genome reference

sequence does not represent an exa

match for any one person's genome.


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Where is this information held?

The National Centre for Biotechnology Information

(NCBI) website (http://www.ncbi.nlm.gov):

Genes and Human Health:

Gene database

OMIM

dbSNP

dbGAP

The Genomic Sequence:

Sequence database (GenBank)

Sequence search tools
http://www.ncbi.nlm.gov/http://www.ncbi.nlm.gov/


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What does the human genome

sequence tell us?

Composition The human genome contains 3 billion nucleotide bases (A, C, T, G).

The average gene consists of 3000 bases, but sizes vary greatly,

with the largest known human gene being dystrophin at 2.4 million

bases.

The total number of genes is estimated at around 30,000 (or as low

as 20-25K --much lower than previous estimates of 80K to 140K.)

Almost all (99.9% was the initial estimate but now thought to be

lower than this) nucleotide bases are exactly the same in all people.

The functions are unknown for over 50% of discovered genes (but

this is decreasing).


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What does the human genome sequence te

us?

Arrangement

The gene-dense "urban centers" are GC-rich

The gene-poor "deserts" are AT-rich regions

Genes appear to be concentrated in random areas along the genome

with vast expanses of noncoding DNA inbetween.

Stretches of up to 30,000 C and G base repeats often occur adjacen

gene-rich areas, forming a barrier between the genes and noncoding

DNA. These CpG islands are believed to help regulate gene activity.

Chromosome 1 has the most genes (2968), and the Y chromosome

has the fewest (231).


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What does the human genome

sequence tell us?

Variations and Mutations

There are over 3 million locations where single-base DNA

differences (SNPs) occur in humans.

This information is revolutionising the processes of finding

chromosomal locations for disease-associated sequences and

tracing human history.


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Human genome sequence variation


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Human Genetic Variation

With the exception of monozygotic

twins,

every one of us is geneticallydifferent from every other human

who ever lived.

How are genomes of individuals different?


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How are genomes of individuals different?

Differences can take the form of substitutions at a single base. These

are called single nucleotide polymorphisms (SNPs)

SNP


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FrequencyExampleRules for assigning allele to classClass of variation

5,692,700(~93%)

A/TSingle base substitution involvingA,T,C, or G

Single NucleotidePolymorphism (SNP)

431,319

(~7%)

T/-CCTA/GDesignated using the full sequence of

the insertion as one allele, and either a

fully defined string for the variant allele

or a - character to specify the

deleted allele.

Deletion/Insertion

Polymorphisms (DIPs)

2,440

(0.04%)

(CAC)8/9/10/11Alleles are designated by providing the

repeat motif and the copy number for

each allele.

Microsatellite or short

tandem repeat (STR)

1,859

(0.03%)

(alu) / -Applies to insertion/deletion

polymorphisms of longer sequence

features, such as retroposondimorphism for Alu or line elements.

Named variant

The Genetic Basis for Human Variation

These frequency figures as of 2005 are now out of date


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Copy Number Variation:

Submicroscopic - 150 kb in

size

Now thought to be morefrequent than SNPs

Impact on disease under

investigation
http://localhost/var/www/apps/conversion/tmp/scratch_5//upload.wikimedia.org/wikipedia/commons/7/72/Gene-duplication.png


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Keeping track of variation

Human Genome Variation Society (HGVS)

Provides guidelines on gene and variation

nomenclature

QUOTE:

In some disciplines the term

"mutation" is used to indicate "a

change" while in other disciplines it is used to indicate "a disease-

causing change". Similarly, the term "polymorphism" is used both

to indicate "a non disease-causing change" or "a change found at a

frequency of 1% or higher in the population". To prevent thisconfusion we do not use the terms mutation and polymorphism

(including SNP or Single Nucleotide Polymorphism) but use neutral

terms like "sequence variant".


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HGVS guidelines for sequence variation nomenclature

Example:

"c." for a coding DNA sequence (like c.76A>T)

nucleotide 1 is the A of the ATG-translation initiation codon

">" indicates a subst i tu t ionat DNA level (like c.76A>T)

(Full guidelines on their webpage: http://www.hgvs.org)


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What is a genetic disease?


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A pathological condition of a part, organ, or

system of an organism resulting from various

causes, such as infection, genetic defect, or

environmental stress, and characterized by

an identifiable group of signs or symptoms.

Standard definition of disease


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Spectrum of Genetic Disease

Mendelian

(single gene)

Multifactorial

(many genes plus environment

factors)

Reduced

penetrance

PKU Multiple

sclerosis

Digenic

RP

Hirsch-

sprung

Crohns

disease


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Classes of genetic conditions

mendelianca. 1% of population

chromosomalca. 1% of newborns

multifactorial or complex5% by age 25, 60% lifetime risk


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The principal disease database: OMIM

Online Mendelian Inheritance in Man (OMIM)

is a comprehensive database for human

genes and genetic disorders, with a focus onmonogenic disorders.

http://www.omim.org/


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Use OMIM

to explore

Rett

syndrome


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There are entriesfor both the

disease and the

gene


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Link to NCBI map viewer

OMIM number


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Allelic variants:


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Patterns of inheritance


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Mendelian inheritance patterns

Autosomal dominant

Autosomal recessive

X-linked recessive/dominantY-linked

Mitochondrial


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Autosomal dominant

Affected males andfemales appear in eachgeneration of thepedigree.

Affected mothers andfathers transmit thephenotype to both sons

and daughters.


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Autosomal dominant inheritance

A t l d i t i h it


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Autosomal dominant inheritancewith reduced penetrance


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Common autosomal dominant conditions

Familial hypercholesterolaemia 143890 1/500

Adult polycystic kidney disease 173900 1/1,000Neurofibromatosis Type 1 162200 1/2,50

Huntington disease 143100 1/3,00

Myotonic dystrophy 160900 1/7,00Familial adenomatous polyposis 175100 1/8,00

Condition MIM # Freq


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The disease appears inmale and femalechildren of unaffected

parents.

Autosomal recessive


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Autosomal recessive inheritance:typical pedigrees

none of the families has any previous history of the disease

Autosomal recessive inheritance


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Autosomal recessive inheritance

in a large multiply inbred kindred


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Common autosomal recessive conditions

Haemochromatosis 235200 1/500

Cystic fibrosis 219700 1/2,00Phenylketonuria 261600 1/10,00

Sickle cell disease 603903 1/250

Thalassaemia 141800, 141900 1/150Tay-Sachs disease 272800 1/1,000



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Many more malesthan females showthe disorder.

All the daughters of

an affected male arecarriers.

None of the sons ofan affected male

show the disorder orare carriers.

X-linked recessive


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X-linked recessive inheritance


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Affected males passthe disorder to alldaughters but to noneof their sons.

Affectedheterozygous femalesmarried to unaffectedmales pass thecondition to half their

sons and daughters

X-linked dominant

C X li k d di i


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Common X-linked conditions

Fragile-X 309550 1/4,00

Duchenne / Becker muscular dystrophy 310200 1/3,00

Retinitis pigmentosa 300389, 312600 1/3,50

Haemophilia A 306700 1/5,000

Haemophilia B 306900 1/30,00


in boys

Y linked transmission


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The main Y gene is called the SRY gene, which is the master gene that specifiesmaleness and male features.

Only men have a Y chromosome and so theY is only passed from father to son

The Y chromosome is relatively small and contains very few genes, there are

relatively few Y-linked disorders.

List of Y-Linked Diseases:

Male Infertility

Excessive hair on the ear pinna (Hypertrichosis pinnae)

A form of Retinitis pigmentosaColour blindness

XYY syndrome

Y-linked transmission


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This type of inheritanceapplies to genes inmitochondrial DNA

Mitochondrial disorderscan appear in everygeneration of a family andcan affect both males andfemales, but fathers donot pass mitochondrialtraits to their children.

Mitochondrial inheritance

MitochondriaMitochondria


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http://www.hopkinsmedicine.org/micfac/beta/images/confocal/actin-mitochondria.jpg

Mitochondria

membrane-enclosed organelle, 110 mm in size generate most of the cell's supply of ATP

separate genome to nuclear genome 1 mitochondria may have up to 10 copies of genome the number in different cells varies (1-1000s) dependent on nuclear genes as well as own genome

Mitochondrial Replication


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Mitochondrial Replication

Mitochondrial DNA is replicated in response to energy needs of

the cell.Growth and division are not linked to the cell cycle

When the energy needs of a cell are high, they grow and divide.When the energy use is low, they are destroyed or become

inactive.

At cell division, mitochondria are distributed to the daughtercells randomly during the division of the cytoplasm.

Mitochondria can fuse and divide: replicating by binary fission

Mitochondrialinheritance


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Egg has about 100,000 molecules of mtDNA and sperm

1001500 mtDNAs

Sperm mitochondria enter the egg during fertilization bare lost soon after

This means your mitochondria all come from your mothe

Mitochondrial disorders are therefore maternallyinherited


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M tochondr al nher tance

Transmitted only by mother

Transmitted to children of both sexes

Often very variable expression

Mitochondrial Disorders


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M D

some neurological disorders e.g stroke like illness

some forms of deafness and blindness

some forms of diabetes mellitus

Deletions, duplications or point mutations in mt-DNA are responsi

for a range of diseases, including :

Mitochondria are heavily dependent on nuclear gene products, sdont assume that any condition with mitochondrial dysfunction mbe caused by a mt-DNA mutation.

For details see www.mitomap.org

some forms of cardiomyopathy

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