Genes and Chromosomes_2010-1

8/2/2019 Genes and Chromosomes_2010-1

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LS2100 Concepts in human genetics, School of Life Sciences, Kingston University

Genes, Chromosomes and the

content of the Human Genome

Scott LawtonEmail: [email protected]

Office hours Monday 11 - 12, Friday 9 - 11


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Navigating the Human Genome


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Learning outcomes

Link DNA with genes and gene structure

Understand the role of chromosomes in

packaging genes

Appreciate the diversity of chromosomes;their structure and function

Familiarise yourself with jargon of themolecular content of the human genome


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Overview of lecture

Revision of DNA structure and content

Structure and function of genes

Packaging of DNA onto chromosomes

Structure and function of chromosomes

Sex chromosomes


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Chromosomes and genetic inheritance

Chromosome theory of inheritance

Mendelian factors - genes arelocated on chromosomes

Not all chromosomes are equal in gene

content

Autosomes Variable number of

genes

X chromosomes gene rich

Y chromosomes - gene poor


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DNA: the building blocks of life?

DNA is self replicating

Gives rise to other

molecules:Transcription/Translation

It can repair itself andform new combinations:

Recombination


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Composition of DNA

4 base pairs

Purines; Adenine and

Guanine Double

ring structure

Pyrimidines; Cytosineand thymine

Helix supported by

the phosphate sugarback bone


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Genes: structure

Genes :

A locatable region of genomic sequence,

corresponding to a unit of inheritance

These are associated with regulatory, transcribed

and other functional regions

ATG TTA AGT CCT GAT GCC TAA AGG GCC TAT GTA TTC GAA TTC TAA TAG

Exon Exon Exon

Codon Codon Codon Codon Codon Codon Codon Codon Codon CodonCodon

Intron Intron


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DNA Packaging on the Chromosomes

First level of packaging DNA windsaround histones to form the nucleosome

Individual nucleosomes are connected

by strands of linker DNA and histones

knowein as linker histone form

chromatin fibres

Next level involves the looped domains of

DNA

- Tens to Hundreds of Kilobase pairs

- Average human chromosome =

2000 looped domains- Domans extend at an angle from

the main chromosome

- Loops anchor on to a filamentous

structure of protein nuclear matrix


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Chromatin

Euchromatin

Makes up the majority of theuncondensed chromosome

Transcriptionally active

Majority of the active genome

Heterochromatin

Remain condensed through outcell cycle

Replicates later than rest ofgenome

Usually transcriptionally inactive

Two types

Constitutional

Facultative


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Chromosome structure

Centromere

Telemere

Sister chromatids

P Arm

Q Arm


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Chromosome diversity

Metacentric Submetacentric Acrotacentric Telocentric


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Human genome: Karyotypes

23 pairs of chromosomes

22 Pairs are homologous

1 pair of sex chromosomes

Females XX

Males XY


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Analysis

Number

Size/ relative size

Chromatin content

Centromere position


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Molecularcytogentics

Fluorescent in

situ hybridisation

BAC landing

Chromosome

painting


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Chromosomal mutations

Deletions

Duplications

Inversions

Insertions

Translocations
http://en.wikipedia.org/wiki/File:Types-of-mutation.png


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Consideration: Human Sex Chromosomes

The sex chromosomes

X chromosome is gene richReproduction

Intelligence

Y chromosomeGene poor

Single male determining

gene (SRY)

Reduced recombination

Highly heterochromatised

and degenerate Y

chromosomes


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Consideration: Human Sex ChromosomesEvolution of sex chromosomes

two homologous chromosomes

One chromosome accumulates mutations that

are beneficial to a single sex

Genes become involved in sex determination

Selection reduces recombination

Heterochromatisation

Inversions

Translocations

Y chromosome is born and begins to degrade

Loses genes

Few genes active

Becomes transcriptionally in active
http://www.rbej.com/content/4/1/59/figure/F15


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Consideration: Human Sex Chromosomes


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Summary

Genes are packaged on to chromosomes Chromosomes are a heritable unit

Karyotype analysis is based on the structure of

a the genome Cytogenetics FISH

Chromosomal mutation

Sex chromosomes unique propertiescompared to the rest of the genome


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Molecular basis of the Human genome

http://www.ncbi.nlm.nih.gov/mapview/map_search.cgi?taxid=9606


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The Human Genome

Most human cells are diploid 2n Somatic cells

Gametes cells are haploid n

2n =46 n=23 Somatic cells derived by mitosis

Gametes derived by meiosis.


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Measuring DNA.

Base pair (bp)

Kilobase pairs (kbpor kb)

Subdivisions ofchromosomes

chromosomes

Genomes

Bases

Sequences

Contigs

Scaffolds

Super Scaffolds

Chromosomes

Genomes


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Types of DNA Sequences

Human genome: 9 x109 bp

/80,000 genes

Two main types of DNA in

human genome

Nuclear

Extranuclear


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Genes

Distribution varies greatly

Few in heterochromatin,majority in sub telomeric

euchromatin

Made up of single copy

genes and multigenefamilies


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Unique single copy genes

Majority of human genes

Code for polypeptides involved in carrying out

a variety of cellular functions

enzymes

hormones

receptors

regulatory proteins

structural proteins


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Multigene families

Many genes have similarfunctions: gene duplicationwith subsequentevolutionary divergence

Often found in clusters eg.Globin gene cluster onchromosome 16

Others widely dispersedthrought the genome eg.

Hox developmental genes.


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Gene Superfamilies

Limited sequence homology but share

functionality often having similar structural

domains.

Examples include the immunoglobulin genes

which are almost certainly derived from

duplication of a precursor gene.


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Extragenic DNA

80,000 genes with an average size of 10-15kb

Account for only 25-35% of the humangenome

The remaining 70% is made up of repetativeDNA sequences which are predominantlytranscriptionally inactive.


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Tandemly repeated DNA sequences

Blocks of highly repetative non coding DNA

which can either be highly dispersed or

restricted in their location in the genome.

Three sub groups

Satellite DNA

Minisatellite DNA

Microsatelite DNA


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Satelite DNA

10 -15% of human genome

Simple short tandemly repeated DNA

sequences

Transcriptionally inactive

Clustered around the centromeres of certain

chromosomes

Named after the characteristics of this type of

DNA in density gradient centrifugation.


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Minisatelite DNA

Two families of transcriptionally inactive

repeated short DNA sequences

Telomeric DNA

The end of telomeres contain 10-15kb of tandem

repeats of a 6bp repeat sequence.

Chromosomal integrity

Telomerase


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Minisatellite DNA

Hypervariable minisateliteDNA

Highly polymorphic

Short tandem repeats of acore sequence

Polymorphism in repeatnumber is the basis forgenetic fingerprinting

(forensic/paternity) Often located close to

telomeres


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Microsatelite DNA

Single, di, tri, or tetranucleotide repeats

located througout the

genome some trinucleotide

repeats are associatedwith genetic diseases

Highly polymorphic andare used to map genes

AAAAAAAAAA

TATATATATATAT

ATCATCATCATC

GTTTGTTTGTTT


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Highly repeated interspersed

repetative DNA sequences.

33% of the human genome

Two types

short interspersed nuclear elements.SINEs

Long interspersed nuclear elements.LINEs


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SINEs

5% of genomes consists of 750,000 copies ofSINEs.

Most common is a 300bp repeat which hassimilarity to a signal recognition particle involved

in protein synthesis They are calledAlu repeats

Retrotransposons are genetic elements that can

amplify themselves in a genome and areubiquitous components of the DNA ofmany eukaryotic organisms.


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LINEs

5% of genome

Most common one is sequence of 6000bp that

occur in about 100 000 copies which encodes

a reverse transcriptase .

Called LINE-1 or L1 element

Mit h d i l DNA


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Mitochondrial DNA

Every cell has several

thousand mitochondria Each mitochondria has

its own 16.6kb circulardouble stranded DNA,

mtDNA It has very little

repetative DNA andcodes for 37 genes

Mitochondria areinherited exclusivelyfrom the oocyte


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Summary

A variety of genes with a variety of functions 1 gene = 1 protein

Majority of the genome is non coding

Vast amounts of the genome is repetitive

Mitochondrial DNA organelle, maternally

inherited

Genes and Chromosomes_2010-1

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