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1.Idiopathic Recurrent Miscarriages Assessment (IRMA)

Approximately 70% of all human fertilizations are naturally aborted, with most occurring before the mother knows she is pregnant. Miscarriages that occur later in pregnancy are often due to non-viable genetic variation and this is very likely in the case of Recurrent Pregnancy Losses (RPL).


Numerical and structural chromosomal abnormalities are routinely investigated to understand causes of RPL, while the study of small-size sequence variants that can impact gene function has been neglected, leaving a whole range of possible causes unexplored.

This project will identify variants severely disrupting genes and regulatory functions, therefore incompatible with life, using whole genome sequence of DNA extracted from chorionic villi of miscarriages collected from women with RPL.

We will identify the highly deleterious dominant mutations as well as rare moderately to highly deleterious recessive mutations that constitute the genetic load of human populations and contribute to miscarriage. Participant inclusion criteria (e.g. recurrence, consanguinity, selection of comorbidities) will ensure the prevalence of genetic over environmental causes, and pre-sequencing screening will exclude cases with large chromosomal aberration.

This project is in collaboration with:

- Michele Rubini, University of Ferrara

- Cesare Furlanello, Fondazione Bruno Kessler

 

REPROS is funded by Merigen Research s.r.l.


 

 

We are interestd in sequencing euploid miscarriages, therfore we do a pre-sequencing screening to exclude aneuploidies and comorbidity. We estimated that 20% of collected samples is euploid. We also find that with current methods it is not possible to make a diagnosis in about 25% of the samples.

2. Genetics of fruit shape and size in peppers

Capsicum fruits are among the most-widely consumed vegetable crops in the world, and one of the most extensively domesticated plants. While a focus of breeding programs and widely studied for its beneficial properties, the genetics of pepper has been studied mostly by linkage analysis and with the use of coarse sets of markers and low resolution phenotypic data.

 

Our collection includes 373 pepper accessions from eleven species from 51 countries. It covers all the economically important species of Capsicum widely used in breeding programs, representing the largest study so far in terms of number of species and number of genetic variants analyzed.

 

This project is a collaboration with Pasquale Tripodi and Nunzio D'Agostino at CREA

 

>>  See our preprint on bioRxive!!  <<

 

>> Go to the project website! <<

We discovered 746k high quality polymorphic sites analyzing sequence data of 373 pepper accessions.

We also measured thirty-eight fruit shape and size attributes in 220 C. annuum accessions.

We used these data to:

(i) uncover genomic properties of the pepper genome

(ii) describe population structure within the Capsicum genus at a resolution never achieved before

(iii) study natural selection,

(iv) discover significant association between genetic markers and traits related to pepper fruit shape and size in C. annuum, including a non-synonymous change in the sequence of longifolia 1-like gene associated with variance in fruit elongation.

3. Positive selction at the ABCA12 gene

 

Natural selection acts on genetic variants by increasing the frequency of alleles responsible for a cellular function that is favorable in a certain environment.

In a previous genome-wide scan for positive selection in contemporary humans, we identified a signal of positive selection in European and Asians at the genetic variant rs10180970. The variant is located in the second intron of the ABCA12 gene, which is implicated in the lipid barrier formation and down-regulated by UVB radiation. Mutations in ABCA12 causes Harlequin Ichthyosis, a rare recessive disorderd with variable penetrance.

We studied the signal of selection in the genomic region surrounding rs10180970 in a larger dataset that includes DNA sequences from ancient samples. We also investigated the functional consequences of gene expression of the alleles of rs10180970 and another genetic variant in its proximity in healthy volunteers exposed to similar UV radiation.

>>  See our preprint on bioRxive!!  <<

 

The Cross Population Extended Haplotype Homozogysity statistic (XP-EHH), measured between pairs of continental populations, shows a signal of positive selection in non-Africans over 35kb downstream rs10180970, especially in East-Asians.

 


4. Deleterious mutations in human consanguineous populations

 

 

We are interested in understanding and characterizing the incidence of deleterious mutations in consanguineous populations.

Alleles with detrimental consequences and recessive inheritance pattern are the major contributors to the genetic load in human populations. Indeed, while dominant deleterious variants are quickly purged by selection, recessive variants remain in the populations at low frequency and mostly in a heterozygosis.

In consanguineous populations kin marriages can cause deleterious recessive variants to be exposed in homozygous state causing higher rate rate of disorders (congenital, late onset, infertility, miscarriage, infant mortality and morbidity). At the same time, however, inbreeding provides an occasion for selection to act on deleterious phenotypes, in a phenomenon known as purging through inbreeding.