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GENOMICA

ASIST. UNIV DR FLORINA MIHAELA NEDELEA


GENOMICA

1. CARTOGRAFIEREA CARACTERELOR MENDELIENE

2. DEZECHILIBRU DE LINKAGE

3. SECVENTIEREA GENOMULUI UMAN SI PROIECTUL GENOMULUI


UMAN

4. NUTRIGENOMICA

5. PROTEOMICA
1. CARTOGRAFIEREA
CARACTERELOR MENDELIENE
Cartografierea genica=determinarea localizarii unei gene pe un
anumit cromozom.

Utilitate:
-intelegerea mecanismelor bolilor genetice,
-diagnosticul bolilor genetice,
-stabilirea riscului de recurenta in familie,
-eventual tratament.
CARTOGRAFIEREA
CARACTERELOR MENDELIENE
Realizarea unei harti complete a genomului uman , o
enciclopedie a tuturor genelor si bolilor genetice associate lor,
a devenit punctual cheie al geneticii .

Cartografierea genelor a fost o etapa prealabila necesara


in abordarea si finalizarea Genomului Uman.

Cartografierea genica =localizarea unor gene care determina boli


monogenice sau susceptibilitate la boala,
Cartografierea genomului uman

Cartografierea genelor pe cromozomii umani s-a realizat folosind


doua metode:

-cartografierea genetica

-cartografierea fizica.
Cartografierea genetica

Cartografierea genetica reprezinta evaluarea tendintei a doua


segmente de ADN, o gena morbida si un marker, de a
segrega impreuna in meioza, si de a se transmite inlantuite de
la parinti la descendenti

Prin studiul fenomenelor de inlantuire si recombinare genica


omoloaga (crossing over in meioza) se poate masura diastanta
intre locii genetici.
Cartografierea genetica

Localizarea unei gene morbide incepe cu studiul familiilor in care


se manifesta boala.

La membrii acestor familii se studiaza distributia bolii si a unor


markeri polimorfi , urmarind inlantuirea intre gene morbida si un
anumit marker. Pentru a fi utili in cartografiere, markerii trebuie
sa fie inalt polimorfi, si astfel creste probabilitatea ca familiile sa
fie informative.

Datorita marimii genomului uman trebuiesc analizati sute de


marker pentru a gasi o inlantuire.
Cartografierea genetica

Daca markerul si gena morbida se afla pe loci foarte apropiati pe


acelasi cromozom, ele au tendinta de a se transmite
impreuna=CO-SEGREGARE.

Daca distanta creste, exista posibilitatea de crossing over si iar


segmentele nealele segrega si se transmit separat, formand
combinatii noi (recombinanti).

Cu cat distanta fizica intre gene este mai mare, cu atat creste
probabilitatea unui eveniment recombinant.
Cartografierea genetica

Distanta intre loci se poate determina comparand genotipurile


urmasilor cu cele ale parintilor si evaluand frecventa (fractia) de
recombinare. Este definita ca scorul LOD(logarithm of
odds)=proportia descendentilor recombinanti/numarul total de
descendenti.
Unitatea de masura intre doi loci=Morgan, in onoarea lui Thomas
Morgan care a descoperit 1910 fenomenul de crossing-over.
Un centiMorgan=distanta genetica in care se produc recombinari
cu frecventa de 1%
1cM echivalent cu o secventa ADN de 1Mb.
Analizele de inlantuire (linkage)

Sunt bazate pe studiul familiilor, reprezinta o metoda valoroasa


de cartografiere deoarece permite stabilirea pozitiei unor gene
(loci) pe acelasi cromozom=SINTENIE, a ordinii si distantei intre
ele.

In present tehnicile noi bazate pe microretele permit testarea


rapida a sute de mii de SNPs-uri raspandite in genom pentru a
urmari CO-SEGREGAREA cu un anumit fenotip (boala).
Inlantuirea genica(linkage)

Genele situate pe acelasi cromozom au tendinta de a se


transmite de la parinti la descendenti, prin gameti, impreuna in
bloc.

Fenomenul prin care genele nealele situate in immediate


proximitate pe acelasi cromozom nu segrega (nu se separa) in
meioza si au tendinta de a se transmite impreuna in succesiunea
generatiilor=inlantuire genica=linkage.

Genele dintr-o regiune cromozomiala care se transmit impreuna


formeaza un grup de inlantuire=haplotip.
Gene alele
Linkage
Inlantuirea genica(linkage)

Fenomenul de inlantuire genica nu este unul abasolut deoarece


numai genele situate foarte aproape una de alta se vor transmite
impreuna (inlantuite ex genele C,D,e ce determina grupul
sangvin Rh localizate pe cromozomul 1 se transmit totdeauna
impreuna).

Pentru genele situate mai la distanta una de alta pe acelasi


cromozom inlantuirea genica poate fi incomplete, ele putand fi
separate prin crossing over.
N Engl J Med.2009 May

Epilepsy, ataxia, sensorineural deafness, tubulopathy,


and KCNJ10 mutations.
Fahad Mahmood,1,Horia C. Stanescu,2,4Jonathan Tobin,4Philip L. Beales,4
Robert Kleta,2,3,4,Detlef Bockenhauer,2,4,andClaire Russell1,,

Recently, we and others elucidated the pathophysiological basis


of a multisystem disorder characterised by infantile-onset
epilepsy, debilitating ataxia, sensorineural deafness and
a salt-wasting tubulopathy, i.e. EAST syndrome (
Bockenhauer et al., 2009;Scholl et al., 2009).
Epilepsy, ataxia, sensorineural
deafness, tubulopathy, and KCNJ10
mutations.
Five children from two consanguineous families presented
with epilepsy beginning in infancy and severe ataxia, moderate
sensorineural deafness, and a renal salt-losing tubulopathy with
normotensive hypokalemic metabolic alkalosis.

We investigated the genetic basis of this autosomal recessive


disease, which we call the EAST syndrome (the presence of
epilepsy, ataxia, sensorineural deafness, and tubulopathy).
Epilepsy, ataxia, sensorineural deafness, tubulopathy,
and KCNJ10 mutations.

Genotypes were examined with the use of a multipoint


parametric linkage analysis and haplotype reconstruction
performed with SimWalk (version 2.91) for an autosomal
recessive model with complete penetrance and a disease allele
frequency of 0.001 (deCode SNP map with Asian allele
frequencies).8
The data were formatted with Mega2 (version 4.0)
through ALOHOMORA (version 0.30, Win32).9,10
Mendelian inconsistencies were checked with the use of
PedCheck (version 1.1); unlikely genotypes were filtered with
the use of Merlin (version 1.1, alpha 3).11,12The SimWalk
haplotype output files were visualized with HaploPainter.
13
Linkage Studies

A haplotype reconstruction (Panel A) for the locus on


chromosome 1 shows identical alleles (indicated by the same
color) in the linked region in all affected patients. The numbers
(i.e., 1 or 2) next to the alleles indicate the respective status of
the single-nucleotide polymorphisms used for genotyping.
Recombinations in Patients 1-1 and 1-2 define this region.
The parametric multipoint linkage analysis of the whole genome
for Family 1 (Panel B) has a single significant peak, with a
maximum lod score of almost 5 on chromosome 1. Genetic
distance (in centimorgans) and individual chromosomes (1 to 22)
are indicated on the lower and upper x axes, respectively.
METHODS:
Whole-genome linkage analysis was performed in the four affected children in
one of the families. Newly identified mutations in a potassium-channel gene
were evaluated with the use of a heterologous expression system. Protein
expression and function were further investigated in genetically modified mice.
RESULTS:
Linkage analysis identified a single significant locus on chromosome
1q23.2 with a lod score of 4.98. This region contained the KCNJ10 gene,
which encodes a potassium channel expressed in the brain, inner ear, and
kidney. Sequencing of this candidate gene revealed homozygous missense
mutations in affected persons in both families. These mutations, when
expressed heterologously in xenopus oocytes, caused significant and specific
decreases in potassium currents. Mice with Kcnj10 deletions became
dehydrated, with definitive evidence of renal salt wasting.
CONCLUSIONS:
Mutations in KCNJ10 cause a specific disorder, consisting of epilepsy,
ataxia, sensorineural deafness, and tubulopathy. Our findings indicate
that KCNJ10 plays a major role in renal salt handling and, hence,
possibly also in blood-pressure maintenance and its regulation.
IDENTIFIED MUTATIONS

Sequencing of the complete coding region ofKCNJ10revealed a


homozygous missense mutation, c.194GC (p.R65P), in the four
affected patients in Family 1 and another homozygous missense
mutation, c.229GC (p.G77R) for Patient 2-1.

Parents were heterozygous for the respective mutations

Supported by the Intramural Research Programs of the National


Human Genome Research Institute, National Institutes of Health, the
Special Trustees of the Great Ormond Street Hospital, St. Peters Trust
for Kidney, Bladder, and Prostate Research, the Grocers Charity, the
David and Elaine Potter Charitable Foundation, and Deutsche
Forschungsgemeinschaft (SFB699).
Generation and validation of a zebrafish model of EAST
(epilepsy, ataxia, sensorineural deafness and tubulopathy)
syndrome
Fahad Mahmood,1,* Monika Mozere,2,* Anselm A. Zdebik,2,3,* Horia C. Stanescu,2,4
Jonathan Tobin,4 Philip L. Beales,4Robert Kleta,2,3,4, Detlef Bockenhauer,2,4,
Generation and validation of a zebrafish model of EAST
(epilepsy, ataxia, sensorineural deafness and tubulopathy)
syndrome
Fahad Mahmood,1,* Monika Mozere,2,* Anselm A. Zdebik,2,3,* Horia C. Stanescu,2,4
Jonathan Tobin,4 Philip L. Beales,4Robert Kleta,2,3,4, Detlef Bockenhauer,2,4,

To test potential therapeutics, suitable disease models are


needed.

Because the mouseKcnj10knockout has a much more severe


phenotype (including brain dysmorphology and neonatal death)
than humans with EAST syndrome, it is not an ideal model.

Here, the authors set out to develop a model of EAST syndrome


using zebrafish, because zebrafish embryos and larvae are ideal
forin vivo, high-throughput drug discovery.
GWAS=genome wide association
studies
Sunt analize de asociere, bazate pe studii populationale.

In acest caz se studiaza frecventa unui set de markeri la un


grup de personae afectate de o anumita boala, comparative cu
un grup de persoane sanatoase.

GWAS sunt utilizate pentru identificarea unor variante genetice


cauzatoare de boli complexe, multifactoriale.
GWAS=genome wide association
studies
GWAS sunt studii bazate pe ipoteza ca variantele alelice ce
determina susceptibiltatea la o boala comuna se asociaza mai
frecvent decat ne asteptam cu anumiti markeri care definesc o
anumita regiune genomica (haplotip).
Identificarea haplotipului asociat bolii permite definirea regiunii in
care este localizata varianta cauzala.
In ultimii ani proiecte international cum sunt Hap Map si
1000Genomes au permis identificarea >18milioane SNPs si
caracterizarea blocurilor de inlantuire genetica=haplotipuri la
indivizi care apartin populatiilor diferite.
Haplotip

Sunt regiuni care se transmit in bloc si in interiorul carora


probabilitatea de recombinare este mica.
Prin GWAS s-au identificat asocierei semnificative a aproximativ
800SNPs ce implica sute de loci in numeroase boli multifactorile.
Astfel s-au identificat gene associate cu degenerescenta
maculara(CFH), boala coronariana (CDKN2A/2B), diabetul zaharat
(TCF7L2, SLC30A8), obezitatea (INSIG2,FTO).
Aplicatiile cartografierii genomului
uman

Cunoasterea organizarii si functionarii aparatului genetic.


Realizarea hartii genice =anatomiagenomului uman.
Elucidarea unor mecanisme patogenice in boli monogenice sau
multifactoriale.
Dezvoltarea de metodologii noi de diagnostic cu ajutorul
markerilor ADN.
Dezvoltarea strategiilor de terapie genica.
2. Dezechilibru de inlantuire

Este o caracteristica populationala, si nu familiala, ce depinde de


distanta genetica intre loci si vechimea mutatiei.

Frecventa teoretica cu care se gasesc anumite haplotipuri in


populatie se calculeaza prin frecventele individuale ale genelor
allele ce-l alcatuiesc. Daca se compara frecventa teoretica cu cea
reala, exista 2 situatii:
Dezechilibru de inlantuire

1. Frecventa reala nu difera semnificativ de frecventa


teoretica=echilibru de inlantuire

2. Daca frecventa reala in populatie a unui anumit haplotip este


mai mare decat frecventa teoretica=se produce o asociere
alelica preferentiala=dezechilibru de inlantuire (linkage
disequilibrium).

Acest lucru se explica prin faptul ca bolnavii au un stramos


comun (efect de fondator).
3.Proiectul Genomului Uman

20 Centre, 6 Tari, inceput 1990


Proiectul Genomului Uman

Lansat in 1990 initial cu o durata de 15ani, Proiectul si-a propus


secventierea genomului uman haploid (22A+X+Y, 3,2Gb),
constand in identificarea si localizarea genelor ce alcatuiesc
genomul.
A implicat 3 etape majore:
1) Secventierea unor fragmente mai mici,
2) Asamblarea genomului cu ajutorul unor programme
computerizate care ordoneaza, orienteaza si asambleaza
secventele segmentelor mici,
3) Adnotarea genomului, identificare elementelor structurale si
atasarea informatiei biologice (functie si expresie) la aceste
elemente =adnotare functionala.
Proiectul Genomului Uman

O prima schitaa genomului uman a fost gata in iunie 2000 si


publicata la 15 februarie 2001 in doua versiuni,
Nature de catre IHGSC
Science de compania privata Celera Genomics.

Ambele versiuni raportau secventierea a 96% din eucromatina


(2,69Gb) si erau incomplete si imperfecte.
Natureon Feb. 15, 2001 (Lander et al., 2001) and Celera Genomics published its draft

sequence in Scienceon Feb. 16, 2001 (Venter et al., 2001)


Francis Sellers Collins (born
April 14, 1950) is an American
physician-geneticist noted for
his discoveries of disease genes
and his leadership of the
Human Genome Project. He is
director of the National
Institutes of Health (NIH) in
Bethesda, Maryland, USA.

Before being appointed director


of the NIH, Collins led the
Human Genome Project and
other genomics research
initiatives as director of the
National Human Genome
Research Institute (NHGRI), one
of the 27 institutes and centers
at NIH
John Craig Venter (born October 14, 1946)
is an American biotechnologist,
biochemist, geneticist, and entrepreneur.
He is known for being one of the first to
sequence the human genome[1] and the
first to transfect a cell with a synthetic
genome.
Venter founded Celera Genomics, The
Institute for Genomic Research (TIGR) and
the J. Craig Venter Institute (JCVI), and is
now CEO of Human Longevity Inc.
Efforts to bring Collins and Venter together to complete the
mapping of the human genome began in late 1999.

In March 2000, US President Bill Clinton and British Prime


Minister Tony Blair made a joint declaration that all genome
information should be free to the public.

This announcement led to cooperation between Collins and


Venter, and on June 26, 2000, Venter and Collins jointly
announced that, after nearly a decade of work, both the public
Human Genome Project headed by Collins and Celera Genomics
headed by Venter had deciphered essentially all the genes in
human DNA.
Proiectul Genomului Uman

Dintre datele obtinute la aceasta prima secventiere a genomului


uman mentionam:
Secventele codante reprezinta <5% din genom, iar
numarul prognozat de gene era 30-35.000.
Astfel genele sunt insule intr-un ocean de ADN necodant.
Asadar genomul nu poate fi considerat ca o simpla
succesiune de gene pe cromozomi, ci o structura cu
arhitectura complexa in care genele sunt dispersate pe
cromozomi si separate prin largi regiuni intergenice,
necodante!
Proiectul Genomului Uman

Numarul genelor la om este relative mic!


Ex 6000 gene-drojdie,
13.000 gene drosofila,
18.000 gene vierme,
26.000 plante.

Diferenta majora la om este reprezentata de complexitatea


proteinelor, structura lor modulara care permite combinatii noi!
Proiectul Genomului Uman

Genomul a doua persoane neinrudite este identic 99,9% din


secventele nucleotidice.
Astfel individualitatea este data de 0,1% (3milioane pb) care
determina variatii personalizate de secventa.

Oamenii difera printr-o pereche de baze(SNPs) la aprox. 1000pb!


Proiectul Genomului Uman

14 aprilie 2003, la 50ani de la descoperirea structurii ADN, a


fost anuntata versiunea aproape completa a genomului uman,
inaugurandu-se era genomicii.
Genome browsers (site-uri de navigatie)

www.ensemble.org
www.ncbi.nlm.nih.gov/genome
www.genome.ucsc.edu
Proiectul Genomului Uman

Informatii aduse de versiunea finisata


Contine aproximativ genele care codifica proteine, dar numarul
lor este mai mic decat in versiunea initial, fiind estimate la 20-
25.000
Cresterea numarului de gene ARN, al caror consecinte medicale
raman a fi elucidate.
O parte majora a ADN-ului necodant , considerat inutil, pare sa
aiba functii importante, neelucidate complet.
Rata mutatiilor la barbat >2x mai mare decat la femei.
Proiectul Genomului Uman

S-a descoperit remarcabila plasticitate a genomului uman,


demonstrandu-se nasterea si moartea genelor umane si
evidentiind duplicatii segmentare.

Prin proiectul ELSI au fost puse in discutie problem etice-protectia


datelor individuale, aspect sociale-inegalitatea de acces la
aplicatiile testelor moleculare,

Aspecte legale-patentarea datelor, metodelor,genelor.


Nasterea si moartea genelor

Plasticitatea remarcabila a genomului uman, demonstrate prin


studiul nasterii si mortiigenelor umane.
Nasterea genelor se face prin duplicatie, cele mai recente
duplicatii intereseaza aprox. 1200 gene, majoritatea fiind genele
receptorilor olfactivi, genele correlate cu imunitatea sau
reproducerea.

Moartea genelor se produce prin mutatii care transforma


genele in pseudogene non-procesate, nefunctionale.
S-au identificat 37gene care au murit recent prin mutatii care
le fac gene nefunctionale!
Nasterea si moartea genelor

Pseudogenele sunt secvente asemanatoare genelor, dar


nefunctionale datorita unor mutatii inactivatoare.

Numarul lor estimate la 12.600!(Ensembl, 2011).

Studii recente in cadrul proiectului ENCODE au aratat ca unele


pseudogene procesate sunt transcrise active si ar putea fi
pseudogene reactivate.
Proiectul Genomului Uman
Totusi dupa publicarea versiunii finisate (2004)
a genomului uman, a urmat resecventierea cu
noi tehnici a fiecarui cromozom.
2006 a fost re-secventiat cromozomul 1,
2007declarata terminate secventa intregului
genom (build 36).
2009 Genome Reference Consortium(GRCh)
publica versiunea a 37-a a genomului uman,
structura sa este aprope complet descifrata.
Proiectul Genomului Uman-
componente
1) ADN-ul genelor care codifica proteine si secvente inrudite
(pseudogene) -1/3
2) ADN-ul extragenic, 2/3, reprezentat de genele ARN,
duplicatii segmentare si AND repetitiv.
Secventele codante transcrise si translatate care corespund
exonilor genelor pentru proteine reprezinta doar 1,1% din
genom.

5% din secventele genomului uman sunt conservate in evolutie,


si sunt reprezentate de elemente functionale de baza-gene care
codifica proteine, ARN, regiuni de reglarea transcriptiei.
Restul genomului =secvente ADN care au evoluat rapid si
divergent.
Inca sunt lucruri de facut

Intelegerea-functiei

-expresiei
-reglarii genelor
-rolul AND-ului intergenic, sunt
date ce trebuiesc completate
-variatiile genetice intre indivizi si
populatii..
Informatii despre fiecare gena-
portaluri Entrez, Ensembl, Gene
Wiki
Gene: NF1ENSG00000196712
Description
neurofibromin 1 [Source:HGNC Symbol;Acc:HGNC:7765]
Synonyms
VRNF, WSS, NFNS
Location
Chromosome 17: 31,094,927-31,382,116forward strand.
GRCh38:CM000679.2
About this gene
This gene has 23 transcripts (splice variants),79 orthologues, is a
member of1 Ensembl protein familyand is associated with88
phenotypes!
NF1 (HGNC Symbol)
CCDS
This gene is a member of the Human CCDS set: CCDS11264.1, CCDS42292.1, CCDS45645.1
UniProtKB
This gene has proteins that correspond to the following UniProtKB identifiers: P21359
RefSeq
Overlapping RefSeq annotation not matched
Overlapping RefSeq Gene ID 4763 matches and has similar biotype of protein_coding
LRG
LRG_214 provides a stable genomic reference framework for describing sequence variants for
this gene
Ensembl version
ENSG00000196712.16
Other assemblies
This gene maps to 29,421,945-29,709,134 in GRCh37 coordinates.
View this locus in the GRCh37 archive: ENSG00000196712
Gene type
Known protein coding
Entrez

NEUROFIBROMIN 1; NF1

Alternative titles; symbols


NEUROFIBROMIN

HGNC Approved Gene Symbol:NF1

Cytogenetic location:17q11.2 Genomic coordinates (GRCh38):


17:31,094,926-31,377,676(from NCBI)
Phenotype Inheritance Phenotype
ocation Phenotype
MIM number (in progress) mapping key

Leukemia, juvenile
607785 SMu,AD 3
myelomonocytic

Neurofibromatosis,
162210 AD 3
familial spinal

17q11.2
Neurofibromatosis, type
162200 AD 3
1

Neurofibromatosis-
601321 AD 3
Noonan syndrome

Watson syndrome 193520 AD 3


Procesul de adnotare structurala si functionala a
genomului uman a generat mai multe proiecte

HapMap=proiect care isi propune realizarea unei harti haplotipice


a genomului uman, care cuprinde modele comune ale variatiei
genetice, in special SNPs, necesare pentru a stabili modul in care
aceste variante pot influenta sanatatea, predispozitia la boli si
raspunsul la factori de mediu si medicamente.
ENCODE= (ENCyclopedia Of Dna Elements)= identificarea si
adnotarea elementelor functionale ale genomului.
Genome 1000=catalog detaliat cu variatiile structurale ale
genomului uman, prin analiza genomurilor a cel putin 1000
persone din grupuri entice diferite.
How We Use This Information?

Better understanding of human disease-importance of


right/wrong diagnosis in life !!!
Personalized medicine & Pharmacogenetics
Greater insight into cognitive function
Insight into human origins
Identifying genetic susceptibility to disease
OMICA
Studiul structurii, organizarii si functiei genomului uman se
numeste genomica.
Proteomul reprezinta ansamblul de proteine sintetizate/exprimate
intr-un organit cellular, celula, tesut, organ care asigura functia
structurii respective.
Proteomica=studiul functiei unor structuri pe baza expresiei
globale a proteinelor (cu ajutorul electroforezei bidimensionale,
cromatografiei, spectometriei de masa)
Genomul este o structura fixa,
Proteomul este dinamic, variaza temporal si spatial si in anumite
conditii de mediu.
Termenul proteome/proteomica
introdus de Mark Wilkins in 1994.
Provocari ale proteomicii/ versus
genomica
1) o gena poate codifica mai mult de o proteina!
Ex genomul uman are aprox 21.000 gene care codifica proteine,
dar numarul total de proteine > 250.000-1.000.000.
2) Proteinele sunt dinamice, interactioneaza, sunt
sintetizate/degradate.
3) Proteinele sufera modificari posttranslationale=pot varia de la
o persoana la alta, in conditii de mediu diferite, sau la aceeasi
persoana in functie de varsta sau medicamente administrate.
4) concentratiile pot fi extreme de variabile. In cancer de
exemplu se crede ca cele mai importante proteine sunt cele in
concentratii foarte mici-dificil de evaluat!
Proteomica
Cand vorbim de proteom ne putem referi la proteomul unei
specii, a unui organ (ex ficat). Proteomul nu este constant, difera
de la celula la celula si se schimba cu timpul.
Mai mult, activitatea proteica este modulate si de alti factori
aditionali genelor.
Proteomica investigheaza:
-unde si cand proteinele sunt exprimate,
-rata de producer/degradare a proteinelor,
-cum sunt proteinele modificate,
Proteomica

-miscarea proteinelor in compartimentele subcelulare,


-implicarea proteinelor in caile metabolice,
-interactiunea proteinelor.
Nature Reviews Cancer(September
2010)
Proteomics-based techniques allow the identification of
biomarkers and protein expression signatures, which could
be used to predict responses to drugs and the clinical
course of disease, and such information could be used to
individualize therapy.
In addition, proteomic techniques are being used to gain an
understanding of how signalling pathways are altered in
tumour cells so that the underlying biology of a human
tumour can be understood.
Moreover, proteomic platforms have been enlisted in drug
development to identify new drugs and to improve our
understanding of how to target various pathways.
Proteomica-medicina fetala

Posibile aplicatii:

-in evaluarea riscului de sarcini cu boli genetice,


-predictia nasterii premature
-preeclampsia
-infectia intraamniotica.
Fetal Diagn Ther 2011

Are Serum Protein Biomarkers Derived from Proteomic


Analysis Useful in Screening for Trisomy 21 at 1113
Weeks? AnnaLuciaMastricci a,b RanjitAkolekar a RameshKuppusamy a
MustafaAhmed a KyprosH.Nicolaides a,b

Conclusion:
Proteins identified as potential biomarkers for trisomy 21 using
proteomic techniques have not been found to be useful in early
screening for this aneuploidy
Studiul PAPR-nasterea prematura

Positive Clinical Validation Data for PreTRM Test Presented at


the Society for Maternal-Fetal Medicines 36th Annual Pregnancy
Meeting 2016

Results from the 5,501-patient Proteomic Assessment of Preterm


Risk (PAPR) study validate the newly available PreTRM test,
which accurately and objectively predicts spontaneous preterm
birth (sPTB), in pregnant women whose blood is drawn for
analysis as early as 19 weeks of pregnancy.
PreTRM Test

PAPR study enrolled 5,501 pregnant women representative of the


United States population.

By taking a novel proteomic approach, this study validated a


signature based on two proteins that are highly predictive of
preterm birth risk: IBP4, insulin-like growth factor binding protein
4, and SHBG, sex-hormone binding globulin.

Using proteomic technology, the PreTRM test measures and


analyzes proteins in the blood that are predictive of preterm
birth.
International Society of Nutrigenetics /
Nutrigenomics

TheInternational Society of Nutrigenetics/Nutrigenomics


(ISNN)was established in 2005, under the Presidency of Artemis P.
Simopoulos, (USA).
NUTRIGENOMICA
Reprezinta aplicarea genomicii, proteomicii, metabolomicii in
cercetari nutritionale, pentru a stabili efectele alimentatiei
asupra functiei genomului precum si actiunile benefice/nocive
ale componentelor dietei la nivel individual sau populational.

Substantele nutritive influenteaza raspunsuri fiziologice ce


afecteaza stabilitatea si expresia genomului sau amprentarea
(imprinting).

Intelegerea acestor mecanisme va ajuta la evaluarea


beneficiilor/riscurilor diferitelor recomandari dietetice, precum si
prevenirea instalarii unor boli, managemetul bolilor cornice.
Nutrigenomica

Principala provocare a cercetarilor din domeniul nutritiei este


complexitatea si dificultatea integrarii factorilor aditionali (stilul de
viata!), care afecteaza rezultatele si fac dificila interpretarea.
Studiile pe termen lung in medicina sunt gold standard.
Studiile nutritionale sunt influentate de complianta redusa pe
termen lung, modificari inevitabile ale stilului de viata.
Dereglarile metabolice sunt recunoscute in multe afectiuni.
Identificarea proceselor metabolice caracteristice bolilor si
dezvoltarea de strategii care blocheaza/corecteaza aceste cai pot
fi o alternative promitatoare in managementul bolii.
Nutrigenomica-cancer
Mai mult anumiti nutrient nu servesc numai ca substrat sau
produsi ai reactiilor enzimatice, dar pot actiona ca si
reglatoriai expresiei genice si pot juca un rol in
modularea cailor metabolice , fie in domeniul preventiei sau
al tratamentului.
In cancer este cunoscuta dereglarea metabolica. Celulele
canceroase preferasa utilizeze anumiti nutrient, ca glucoza si
glutamatul ca sursa de energie. De asemenea metabolismul
lipidic este crescut rezultand mediatori ca eicosanoizi, ce creeaza
un micromediu suportiv celulelor tumorale.
Folosind nutrienti care pot modula aceste cai si sa interfere cu
particularitatile metabolice din cancer, interventiile nutritionale
sunt astfel capabile sa inhibe dezvoltatrea celulelor canceroase.
Nutrigenomica

Mai mult fata de tratamentele conventionale, nutrientii pot fi


combinati sigur/sau pot exista in natura combinatii effective
pentru tinte multiple!
Effects of a High-Protein/Low-Carbohydrate Diet versus a
Standard Hypocaloric Diet on Weight and Cardiovascular Risk
Factors: Role of a Genetic Variation in the rs9939609FTOGene
de Luis D.A, Romero
J Nutrigenet E
Nutrigenomics 2015;8:128-
136
(DOI:10.1159/000441142)
The common polymorphism rs9939609 of the fat mass- and
obesity-associated gene(FTO)has been linked to obesity. Our
aim was to investigate its role in weight loss after the
administration of a high-protein/low-carbohydrate diet compared
to a standard hypocaloric diet (1,000 kcal/day)

Weight loss was better in A allele carriers than


noncarriers, and metabolic improvement was better with
the HP diet.
Nutrigenomica
All humans have the same set of genes.
Our differences come from the tinyvariationsin those genes.
Those variations influence not only in how you look or
behave different to others But in how your body reacts
differently to external factors.
Especially how it reacts to the foods you eat and lifestyle you
live.
For example, some have great difficulty metabolising caffeine.
For others, it could be alcohol.
Some have issues that increases their risk of Alzheimers
disease,known as APOE4.
Nutrigenomics: The GenomeFood
Interface
M. Nathaniel Mead,2007
Nutrigenomics therefore initially referred to the study of the
effects of nutrients on the expression of an individuals genetic
makeup. More recently, this definition has been broadened to
encompass nutritional factors that protect the genome from
damage. Ultimately, nutrigenomics is concerned with the impact
of dietary components on the genome, the proteome (the sum
total of all proteins), and the metabolome (the sum of all
metabolites).
As in pharmacogenomics, where a drug will have diverse impacts
on different segments of the population, researchers recognize
that only a portion of the population will respond positively to
specific nutritional interventions, while others will be
unresponsive, and still other could even be adversely affected.
J Nutrigenet Nutrigenomics 2016;9:65-82
(DOI:10.1159/000445996)

Bovine Mammary Nutrigenomics and Changes in the Milk


Composition due to Rapeseed or Sunflower Oil
Supplementation of High-Forage or High-Concentrate
Diets
Leroux C.Bernard L.Faulconnier Y.Rouel J.de la Foye
A.Domagalski J.Chilliard Y.
Fatty acid (FA) composition plays a crucial role in milk nutritional
quality. Despite the known nutritional regulation of ruminant milk
composition, the overall mammary mechanisms underlying this
regulation are far from being understood. The aim of our study
was to determine nutritional regulation of mammary
transcriptomes in relation to the cow milk composition
Our results showed a higher amplitude of milk composition and
mammary transcriptome responses to lipid supplementation with
the LF-SO compared with the LF diet than with the HF-RS
compared with the HF diet. Forty-nine differentially
expressed genes, including genes involved in lipid metabolism,
were identified with LF-SO versus LF, whereas RS
supplementation to the HF diet did not affect the mammary
transcriptome.

Conclusions:This study highlights different responses to lipid


supplementation of milk production and composition and
mammary transcriptomes depending on the nature of lipid
supplementation and the percentage of dietary concentrate.
Nutrigenomics and metabolomics will change clinical nutrition
and public health practice: insights from studies on dietary
requirements for choline2
Steven H Zeisel,
Am J Clin Nutr
Investigators found longer survival and a 75% lower risk of
diabetes mellitus in humans whose paternal grandfathers
experienced food scarcity during the slow growth period just
before puberty than in those whose paternal grandfathers did not
(3032). Pembrey (32) effectively argued that these effects of
nutrition must occur via epigenetic imprinting of paternal genes
and pointed out that the slow growth period before puberty
occurs when the first viable pools of spermatocytes emerge and
when reprogramming of DNA methylation imprinting begins. In a
similar fashion, epi-genetic events can modulate carcinogenesis
in the adult;
NATURE REVIEWS ENDOCRINOLOGY|REVIEW
Personalized weight loss strategiesthe role of macronutrient distribution
J.AlfredoMartinez
Nature Reviews Endocrinology 14 October 2014

The causes of variation in individual responses to various diets are


currently under debate, and some evidence suggests that differences
are associated with specific genotypes.

The initial findings of research into personalized nutrition, based on


the interactions of macronutrient intake and genetic background and its
potential influence on dietary intervention strategies.
http://www.dietvsdisease.org/
MTHFR Mutation

So without the enzyme activity of MTHFR, methylation of folate


and folic acidcannot occur properly.
The two main functional mutations (also known as
polymorphisms) of the gene are
MTHFR C677T and MTHFR A1298C.
Specifics aside, these genetic mutations are collectively known
asMTHFR mutations.They can be like a defect which limits
production of your MTHFR enzymes.
Its important that MTHFR mutation itself isnot inherently
dangerous but any form of genetic variance has the possibility
to affect health!
MTHFR Mutation

Those with an MTHFR mutation are at risk for poor MTHFR


enzyme efficiency.
Consequently, folate and folic acid cannot be efficiently
converted into their active form, known as5-MTHFor L-
methylfolate. Therefore those nutrients cant perform one of their
key functions:breaking down (recycling) Homocysteine.
Homocysteineis an amino acid thought to damage the lining of
your arteries and other cells of the body. It is naturally formed in
the body, but gets broken down by 5-MTHF.
Elevated homocysteine levels in the blood is
anindependentrisk factor for heart disease,
MTHFR Mutation

Those with an MTHFR mutation may be predisposed to


increased levels of homocysteine, a strong risk factor for
cardiovascular disease.

They are also more likely to develop a folate deficiency if their


diet is not rich in folate!
MTHFR Mutation
Daily intake for folic acid is 400 g.
Folic acid is the conventional supplement for treating B-vitamin
deficiency, lowering homocysteine levels, and reducing the
incidence ofNeural Tube Defects!
It is so effective that the addition of folic acid back into to wheat
flour is now mandatory in Australia, USA, Canada and several
other countries.
FDAandEuropean Food Standards Agencyhave approved
several products containing 5-MTHF.
Va multumesc!