Decoupling mutational processes in human germline презентация

Июль 29, 2022

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Биология
Decoupling mutational processes in human germline

Содержание

2. DNA and it’s function DNA double stranded molecule Each strand have direction DNA->RNA->Protein
3. Transcription and replication DNA->RNA DNA->DNA 3` 5`
4. Germline mutations Goriely, Nat. Gen. 2016
5. Role of mutations in genetic disease Kosmicki et al, Nature Genetics 2017
6. Germline mutations are induced by a mixture of mutational processes Mutational processes Observed mutations Mutational spectra
7. Spatial variation in intensity of the mutational processes generates diverse mutational patterns
8. Extracting mutational processes from the spatial variation I #Regions #Signatures
9. Manifestation of strand dependent and independent mutational processes
10. Mutational asymmetry in genes Marteijn et al 2014, Nat. Rev Mol. Cell. Bio Hu et al,
11. Manifestation of strand dependent and independent mutational processes Genes Mutations
12. What do we find?
13. Replication Program Arneodo lab, Plos Comp 2012
14. What do we find
15. Process 7/8 have local bursts
16. Process 7/8 – maternal signature Goldman*, Seplyarskiy*, Wong* et al, 2018 Nature Genetics Jónsson et al,
17. We are able to predict genomic regions susceptible to maternal clusters
18. Process 7/8– maternal signature Goldman*, Seplyarskiy*, Wong* et al, 2018 Nature Genetics
19. Process 7/8 asymmetric in respect to transcription
20. Process 7/8 asymmetric in respect to transcription
21. Mechanistic insights to maternal signature Goldman*, Seplyarskiy*, Wong* et al, 2018 Nature Genetics I was proven
22. C>G mutations created by secondary mechanism (wrong already) Clustered mutation contain few C>G substitutions, But started
23. Third of maternal age effect localized in the regions with high level of the process 7/8
24. Signatures 4 and 5 (maternal signatures) summary Maternal signature sensitive to the direction of transcription and
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Слайд 2

DNA and it’s function
DNA double stranded molecule
Each strand have direction
DNA->RNA->Protein

Слайд 3

Transcription and replication
DNA->RNA
DNA->DNA
3`
5`

Слайд 4

Germline mutations
Goriely, Nat. Gen. 2016

Слайд 5

Role of mutations in genetic disease
Kosmicki et al, Nature Genetics 2017

Слайд 6

Germline mutations are induced by a mixture of mutational processes
Mutational
processes
Observed mutations
Mutational
spectra

Слайд 7

Spatial variation in intensity of the mutational processes generates diverse mutational patterns

Слайд 8

Extracting mutational processes from the spatial variation
I
#Regions
#Signatures

Слайд 9

Manifestation of strand dependent and independent mutational processes

Слайд 10

Mutational asymmetry in genes
Marteijn et al 2014, Nat. Rev Mol. Cell. Bio

Hu et al, 2017 PNAS

Слайд 11

Manifestation of strand dependent and independent mutational processes
Genes
Mutations

Слайд 12

What do we find?

Слайд 13

Replication Program
Arneodo lab, Plos Comp 2012

Слайд 14

What do we find

Слайд 15

Process 7/8 have local bursts

Слайд 16

Process 7/8 – maternal signature
Goldman, Seplyarskiy, Wong* et al, 2018 Nature Genetics
Jónsson et

al, 2017 Nature

Слайд 17

We are able to predict genomic regions susceptible to maternal clusters

Слайд 18

Process 7/8– maternal signature
Goldman, Seplyarskiy, Wong* et al, 2018 Nature Genetics

Слайд 19

Process 7/8 asymmetric in respect to transcription

Слайд 20

Process 7/8 asymmetric in respect to transcription

Слайд 21

Mechanistic insights to maternal signature
Goldman, Seplyarskiy, Wong* et al, 2018 Nature Genetics
I was

proven wrong
Marteijn et al 2014, Nat. Rev Mol. Cell. Bio

Слайд 22

C>G mutations created by secondary mechanism (wrong already)
Clustered mutation contain few C>G substitutions,

But started with different mutation type

Слайд 23

Third of maternal age effect localized in the regions with high level of

the process 7/8

Слайд 24

Signatures 4 and 5 (maternal signatures) summary
Maternal signature sensitive to the direction of

transcription and replication (no evidence for DNA breaks)
Characteristic scale of the signature about 20Mb, but highest intensity achieved on non-transcribed strand of long genes
We find evidence for transcription associated mutagenesis
Maternal signature is by product of the activity of error-prone polymerase

Insights about maternal signature