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Mouse genome
1. They have similarity with humans in terms of anatomy, physiology
and genetics.
2. They are cost effective, because they are cheap and easy to look
after.
3. Adult mice multiply quickly. They can reproduce as often as three
weeks.
4. The time between a mouse being born and giving birth (generation
time) is short, usually around 10 weeks. This means several
generations can be observed at once.
5. The mouse has a short lifespan (one mouse year equals about 30
human years) which means scientists can easily measure the effects
of ageing.
Mus Musculus
Figure: Scientific classification Figure: Two day old pupFigure: One day old pups
FACTS:
1. Breeding onset occurs at 50 days of age for both males and females.
2. The average gestation period is 20 days.
3. The average little size is 10-12 during optimum production.
4. The young are called pups and weigh 0.5 to 1.5 grams at birth.
(https://en.wikipedia.org/wiki/House_mouse)
STRAINS:
 There are over 3000 genetically defined strains, including:-
 Inbred Mice:
Results from 20 consecutive generations of brother and sister mating.
eg: C57BL/6, BALB/c, C3H, FVB, 129, DBA, CBA etc.
Hybrid Mice:
These are F1 crosses between two different inbred strains.
 Recombinant inbred Mice:
Results from 20 generations of brother and sister mating starting from F2.
 Coisogenic strains:
They differ from each other only at one genes
 Transgenic mice:
Carry foreign DNA.
 Knockout Mice:
Mice have 19 autosomes (compared to 22 in humans), and
have the centromere at the end, rather than the middle of the
chromosome (acrocentric).
The order and arrangement of genes on the chromosomes is
not the same as in humans, although there is often local
conservation between the species
Maximum no.
of genes.
Minimum
no. of
genes.
Origins of mouse genomics
The Human Genome Project (HGP) was launched in 1990, it
included the mouse as one of its five central model organisms, and
targeted the creation of genetic, physical and eventually sequence
maps of the mouse genome.
By 1996, a dense genetic map with nearly 6,600 highly
polymorphic SSLP markers ordered in a common cross had been
developed providing the standard tool for mouse genetics.
Physical maps of the mouse genome also proceeded apace,
using sequence-tagged sites (STS) together with radiation-hybrid
panelsand yeast artificial chromosome (YAC) libraries to construct
dense landmark maps.
In 2003 MGSC reported a draft sequence of mouse.
Mouse Genome Sequencing Consortium
The International Mouse Genome Sequencing Consortium
sequenced and analyzed more than 95 percent of the genetic
code of Mus musculus, which contains about 2.5 billion DNA
base pairs compared to 2.9 billion in the human genome.
The MGSC originally consisted of three large sequencing centres
• The Whitehead/Massachusetts Institute of Technology (MIT)
Center for Genome Research
• The Washington University Genome Sequencing Centre
• The Wellcome Trust Sanger Institute—together with an
international database, Ensembl, a joint project between the
European Bioinformatics Institute and the Sanger Institute.
Sequencing strategy
The ultimate aim was to produce a finished, richly annotated
sequence of the mouse genome to serve as a permanent
reference for mammalian biology.
The strategy has four components:
(1) production of a BAC-based physical map of the mouse genome
by fingerprinting and sequencing the ends of clones of a BAC
library;
(2) WGS (whole genome shotgun) sequencing to approximately
sevenfold coverage and assembly to generate an initial draft
genome sequence;
(3) Hierarchical shotgun sequencing of BAC clones covering the
mouse genome combined with the WGS data to create a hybrid
WGS-BAC assembly; and
(4) Production of a finished sequence by using the BAC clones as a
template for directed finishing.
Sequencing and Assembly
Female mice of the C57BL/6J strain was used for sequencing.
The genome assembly was based on a total of 41.4 million
sequence reads derived from both ends of inserts (paired-end
reads) of various clone types prepared from B6 female DNA.
 The inserts ranged in size from 2 to 200 kb.
A total of 33.6 million reads passed extensive checks for quality
and source, of which 29.7 million were paired; that is, derived from
opposite ends of the same clone.
The assembled reads represent approximately 7.7-fold sequence
coverage of the euchromatic mouse genome.
Together, the clone inserts provide roughly 47-fold physical
coverage of the genome.
The assembly contains 224,713 sequence contigs, which are
connected by at least two read-pair links into supercontigs (or
scaffolds).
supercontigs (scaffolds) were aligned to possible chromosomal
locations in the proper order and orientation.
 Supercontigs were localized largely by sequence alignments
with the extensively validated mouse genetic map with some
additional localization provided by the mouse radiation-hybrid
mapand the BAC map
Mouse genome
Mouse genome
(https://www.broadinstitute.org/mouse/mouse-genome-project)
Similarities and differences between the human and
mouse genomes.
The mouse genome is about 14% smaller than the human
genome (2.5 Gb compared with 2.9 Gb). The difference probably
reflects a higher rate of deletion in the mouse lineage.
Over 90% of the mouse and human genomes can be
partitioned into corresponding regions of conserved synteny,
reflecting segments in which the gene order in the most recent
common ancestor has been conserved in both species.
At the nucleotide level, approximately 40% of the human
genome can be aligned to the mouse genome. These sequences
seem to represent most of the orthologous sequences that
remain in both lineages from the common ancestor, with the rest
likely to have been deleted in one or both genomes.
The mouse and human genomes each seem to contain about
30,000 protein-coding genes. The proportion of mouse genes with
a single identifiable orthologue in the human genome seems to be
approximately 80%.
Mouse–human sequence comparisons allow an estimate of the
rate of protein evolution in mammals. Certain classes of secreted
proteins implicated in reproduction, host defence and immune
response seem to be under positive selection, which drives rapid
evolution.
Despite marked differences in the activity of transposable
elements between mouse and human, similar types of repeat
sequences have accumulated in the corresponding genomic
regions in both species. The correlation is stronger than can be
explained simply by local (G+C) content and points to additional
factors influencing how the genome is moulded by transposons..
By additional sequencing in other mouse strains, about 80,000
single nucleotide polymorphisms (SNPs) have been identified. The
distribution of SNPs reveals that genetic variation among mouse
strains occurs in large blocks.
Conservation of synteny between human and mouse
A typical 510-kb segment of mouse chromosome 12 that shares common
ancestry with a 600-kb section of human chromosome 14 is shown.
Segments and blocks >300 kb in size with conserved synteny in
human are superimposed on the mouse genome.
Dot plots of conserved syntenic segments in three human and three mouse
chromosomes.
(G+C) content
The overall distribution of local (G+C) content is significantly
different between the mouse and human genomes. Such
differences have been noted in biochemical studies
Mouse has a higher mean (G+C) content
than human (42% compared with 41%).
Mouse genome
Human genome
CpG islands
Computer program can be used that attempts to recognize CpG
islands on the basis of (G+C) and CpG content of arbitrary lengths
of sequence to the non-repetitive portions of human and mouse
genome sequences.
The mouse genome contains fewer CpG islands than the human
genome (about 15,500 compared with 27,000).
Repeats
The single most prevalent feature of mammalian genomes is
their repetitive sequences.
All mammals have four classes of transposable elements:
(1) The autonomous long interspersed nucleotide element (LINE)
(2) Short RNA-derived short interspersed nucleotide elements
(SINEs);
(3) Retrotransposons
(4) DNA transposons.
Correlation of SINEs and LINEs in human and mouse orthologous
regions
Evolution of the Mouse Genome – SNP Deserts and
Gene Deserts
The availability of a draft sequence of the mouse genome
immediately initiated a comprehensive genome-wide study of
sequence variation between mouse inbred strains.
The common lab inbred strains were derived from a limited
number of ancestral progeny.
These strains have been of enormous utility in analysing and
mapping the genetic loci determining a whole range of biological
and disease phenotypes.
The search for sequence variants (SNPs) between the inbred
strains has two potential applications.
1) Allows us to look back in time at the relationship between the
various inbred strains and assess their origins and divergence.
2) It enables us to identify regions of the genome that may
underlie the common phenotypic characteristics of groups of
inbred strains.
What am I
doing with
my life?
What are you
doing with my
life?

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Mouse genome

  • 2. 1. They have similarity with humans in terms of anatomy, physiology and genetics. 2. They are cost effective, because they are cheap and easy to look after. 3. Adult mice multiply quickly. They can reproduce as often as three weeks. 4. The time between a mouse being born and giving birth (generation time) is short, usually around 10 weeks. This means several generations can be observed at once. 5. The mouse has a short lifespan (one mouse year equals about 30 human years) which means scientists can easily measure the effects of ageing.
  • 3. Mus Musculus Figure: Scientific classification Figure: Two day old pupFigure: One day old pups FACTS: 1. Breeding onset occurs at 50 days of age for both males and females. 2. The average gestation period is 20 days. 3. The average little size is 10-12 during optimum production. 4. The young are called pups and weigh 0.5 to 1.5 grams at birth. (https://en.wikipedia.org/wiki/House_mouse)
  • 4. STRAINS:  There are over 3000 genetically defined strains, including:-  Inbred Mice: Results from 20 consecutive generations of brother and sister mating. eg: C57BL/6, BALB/c, C3H, FVB, 129, DBA, CBA etc. Hybrid Mice: These are F1 crosses between two different inbred strains.  Recombinant inbred Mice: Results from 20 generations of brother and sister mating starting from F2.  Coisogenic strains: They differ from each other only at one genes  Transgenic mice: Carry foreign DNA.  Knockout Mice:
  • 5. Mice have 19 autosomes (compared to 22 in humans), and have the centromere at the end, rather than the middle of the chromosome (acrocentric). The order and arrangement of genes on the chromosomes is not the same as in humans, although there is often local conservation between the species
  • 7. Origins of mouse genomics The Human Genome Project (HGP) was launched in 1990, it included the mouse as one of its five central model organisms, and targeted the creation of genetic, physical and eventually sequence maps of the mouse genome. By 1996, a dense genetic map with nearly 6,600 highly polymorphic SSLP markers ordered in a common cross had been developed providing the standard tool for mouse genetics. Physical maps of the mouse genome also proceeded apace, using sequence-tagged sites (STS) together with radiation-hybrid panelsand yeast artificial chromosome (YAC) libraries to construct dense landmark maps. In 2003 MGSC reported a draft sequence of mouse.
  • 8. Mouse Genome Sequencing Consortium The International Mouse Genome Sequencing Consortium sequenced and analyzed more than 95 percent of the genetic code of Mus musculus, which contains about 2.5 billion DNA base pairs compared to 2.9 billion in the human genome. The MGSC originally consisted of three large sequencing centres • The Whitehead/Massachusetts Institute of Technology (MIT) Center for Genome Research • The Washington University Genome Sequencing Centre • The Wellcome Trust Sanger Institute—together with an international database, Ensembl, a joint project between the European Bioinformatics Institute and the Sanger Institute.
  • 9. Sequencing strategy The ultimate aim was to produce a finished, richly annotated sequence of the mouse genome to serve as a permanent reference for mammalian biology. The strategy has four components: (1) production of a BAC-based physical map of the mouse genome by fingerprinting and sequencing the ends of clones of a BAC library; (2) WGS (whole genome shotgun) sequencing to approximately sevenfold coverage and assembly to generate an initial draft genome sequence; (3) Hierarchical shotgun sequencing of BAC clones covering the mouse genome combined with the WGS data to create a hybrid WGS-BAC assembly; and (4) Production of a finished sequence by using the BAC clones as a template for directed finishing.
  • 10. Sequencing and Assembly Female mice of the C57BL/6J strain was used for sequencing. The genome assembly was based on a total of 41.4 million sequence reads derived from both ends of inserts (paired-end reads) of various clone types prepared from B6 female DNA.  The inserts ranged in size from 2 to 200 kb. A total of 33.6 million reads passed extensive checks for quality and source, of which 29.7 million were paired; that is, derived from opposite ends of the same clone. The assembled reads represent approximately 7.7-fold sequence coverage of the euchromatic mouse genome.
  • 11. Together, the clone inserts provide roughly 47-fold physical coverage of the genome. The assembly contains 224,713 sequence contigs, which are connected by at least two read-pair links into supercontigs (or scaffolds). supercontigs (scaffolds) were aligned to possible chromosomal locations in the proper order and orientation.  Supercontigs were localized largely by sequence alignments with the extensively validated mouse genetic map with some additional localization provided by the mouse radiation-hybrid mapand the BAC map
  • 15. Similarities and differences between the human and mouse genomes. The mouse genome is about 14% smaller than the human genome (2.5 Gb compared with 2.9 Gb). The difference probably reflects a higher rate of deletion in the mouse lineage. Over 90% of the mouse and human genomes can be partitioned into corresponding regions of conserved synteny, reflecting segments in which the gene order in the most recent common ancestor has been conserved in both species. At the nucleotide level, approximately 40% of the human genome can be aligned to the mouse genome. These sequences seem to represent most of the orthologous sequences that remain in both lineages from the common ancestor, with the rest likely to have been deleted in one or both genomes.
  • 16. The mouse and human genomes each seem to contain about 30,000 protein-coding genes. The proportion of mouse genes with a single identifiable orthologue in the human genome seems to be approximately 80%. Mouse–human sequence comparisons allow an estimate of the rate of protein evolution in mammals. Certain classes of secreted proteins implicated in reproduction, host defence and immune response seem to be under positive selection, which drives rapid evolution. Despite marked differences in the activity of transposable elements between mouse and human, similar types of repeat sequences have accumulated in the corresponding genomic regions in both species. The correlation is stronger than can be explained simply by local (G+C) content and points to additional factors influencing how the genome is moulded by transposons..
  • 17. By additional sequencing in other mouse strains, about 80,000 single nucleotide polymorphisms (SNPs) have been identified. The distribution of SNPs reveals that genetic variation among mouse strains occurs in large blocks. Conservation of synteny between human and mouse A typical 510-kb segment of mouse chromosome 12 that shares common ancestry with a 600-kb section of human chromosome 14 is shown.
  • 18. Segments and blocks >300 kb in size with conserved synteny in human are superimposed on the mouse genome.
  • 19. Dot plots of conserved syntenic segments in three human and three mouse chromosomes.
  • 20. (G+C) content The overall distribution of local (G+C) content is significantly different between the mouse and human genomes. Such differences have been noted in biochemical studies Mouse has a higher mean (G+C) content than human (42% compared with 41%). Mouse genome Human genome
  • 21. CpG islands Computer program can be used that attempts to recognize CpG islands on the basis of (G+C) and CpG content of arbitrary lengths of sequence to the non-repetitive portions of human and mouse genome sequences. The mouse genome contains fewer CpG islands than the human genome (about 15,500 compared with 27,000). Repeats The single most prevalent feature of mammalian genomes is their repetitive sequences. All mammals have four classes of transposable elements: (1) The autonomous long interspersed nucleotide element (LINE) (2) Short RNA-derived short interspersed nucleotide elements (SINEs); (3) Retrotransposons (4) DNA transposons.
  • 22. Correlation of SINEs and LINEs in human and mouse orthologous regions
  • 23. Evolution of the Mouse Genome – SNP Deserts and Gene Deserts The availability of a draft sequence of the mouse genome immediately initiated a comprehensive genome-wide study of sequence variation between mouse inbred strains. The common lab inbred strains were derived from a limited number of ancestral progeny. These strains have been of enormous utility in analysing and mapping the genetic loci determining a whole range of biological and disease phenotypes. The search for sequence variants (SNPs) between the inbred strains has two potential applications. 1) Allows us to look back in time at the relationship between the various inbred strains and assess their origins and divergence. 2) It enables us to identify regions of the genome that may underlie the common phenotypic characteristics of groups of inbred strains.
  • 24. What am I doing with my life? What are you doing with my life?

Editor's Notes

  • #3: Mice are extremely useful for studying complex diseases, such as atherosclerosis and hypertension, as many of the genes responsible for these diseases are shared between mice and humans. Research in mice provides insights into the genetic risk factors for these diseases in the human population. It is relatively easy to manipulate the mouse genome, for example, adding or removing a gene to better understand its role in the body. This provides a powerful tool for modelling specific diseases when a mutated gene is known to play a role in the disease. Immunodeficient mice can also be used as hosts to grow both normal and diseased human tissue. This has been a useful tool in cancer and AIDS research.  Inbred strains are well-characterized, genetically uniform mouse models that can be used for a wide variety of human biological and disease research.
  • #6: The haploid genome is about 3 billion base pairs long. (2818.97 Mb size) Mice have 20 chromosomes in their haploid genome. The current count of primary coding genes in lab mouse is 24,500. They have a GC % of about 41.95% N50 is defined as the sequence length of the shortest contig at 50% of the total genome length. For example, consider 9 contigs with the lengths 2,3,4,5,6,7,8,9,and 10; their sum is 54, half of the sum is 27, and the size of the genome also happens to be 54. 50% of this assembly would be 10 + 9 + 8 = 27 (half the length of the sequence). Thus the N50=8, which is the size of the contig which, along with the larger contigs, contain half of sequence of a particular genome. Note: When comparing N50 values from different assemblies, the assembly sizes must be the same size in order for N50 to be meaningful
  • #8: A contig is the assembly of overlapping clones without a gap, i.e. the unbroken series of clones assembled using overlapping sequences. The N50 is defined as the minimum contig length needed to cover 50% of the genome.  Example For an assembly fragmented into 4 contigs with lengths: 1, 2, 4, and 5 kb (total size = 12 kb), half of the genome length is covered by the two largest contigs, and hence N50=4kb is the minimum contig length required to cover 50 percent of the assembled genome sequence. N10 is the minimum contig length to cover 10 percent of the genome. N90 is the minimum contig length to cover 90 percent of the genome.
  • #9: In fact, only about 300 genes are unique to either organism, which further supports the use of the mouse models for studying various diseases as well as testing novel treatments. The key differences lie in those areas of the genome governing immunity, detoxification, smell and sex, which makes sense considering where rodents usually live, how they find food and the number of offspring they can produce. the Broad Institute has been generating a map of single-nucleotide polymorphisms (SNPs) among mouse strains. The initial set contains ~340,000 SNPs and has been used to characterize the haplotype structure of the laboratory mouse. The current goal is a dense haplotype map (20 kb resolution) of 48 mouse strains, as well as an in-depth characterization of variation within 15 mouse strains.
  • #10: This mixed strategy was designed to exploit the simpler organizational aspects of WGS assemblies in the initial phase, while still culminating in the complete high-quality sequence afforded by clone-based maps.
  • #16: the mouse and human genomes have each been shuffled by chromosomal rearrangements. The rate of these changes, however, is low enough that local gene order remains largely intact. It is thus possible to recognize syntenic (literally ‘same thread’) regions in the two species that have descended relatively intact from the common ancestor.
  • #18: Human chromosome 20 corresponds entirely to a portion of mouse chromosome 2, with nearly perfect conservation of order along almost the entire length, disrupted only by a small central segment (Fig. 4a, d). Human chromosome 17 corresponds entirely to a portion of mouse chromosome 11, but extensive rearrangements have divided it into at least 16 segments (Fig. 4b, e). Other chromosomes, however, show evidence of much more extensive interchromosomal rearrangement than these cases 
  • #22: L1 seems to have remained highly active in mouse, whereas it has declined in the human lineage. only a single SINE (Alu) was active in the human lineage, the mouse lineage has been exposed to four distinct SINEs (B1, B2, ID, B4). Each is thought to rely on L1 for retroposition, although none share sequence similarity, as is the rule for other LINE–SINE pairs Only four lineage-specific DNA transposon families could be identified in mouse (the mariner element MMAR1, and the hAT elements URR1, RMER30 and RChar1), compared with 14 in the primate lineage.
  • #24: Comparisons of sequence from inbred strains demonstrate that the level of sequence differences between any two inbred strains varies enormously between different regions of the genome [24–26]. In some regions, the frequency of SNPs is as high as 1 in 250 bp. Other regions are relatively devoid of sequence variants and the SNP frequency is as low as 1 in 20 kb – the so-called SNP deserts. It is assumed that these deserts represent ancestral regions shared by the founder mice that were used to estab-lish most inbred strains.