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Stem cell-based organoid models of neurodevelopmental disorders

In this talk, I will present our latest findings on modeling focal cortical dysplasia (FCD), a highly epileptogenic neurodevelopmental disease, using a human in vitro brain model. Our model is based on induced stem cells from FCD patients, allowing us to preserve the patients' genetic information. We were able to recapitulate cell abnormalities, including dysmorphic neurons, balloon cells, and impaired cell proliferation, with the key role of adherens junctions. Our model paves the way for pursuing drug screening and personalized medicine for FCD patients.

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The Brazilian Rare Genomes Project: bringing the power of genomics to the public health service - João Bosco

In this talk we will describe the largest Brazilian project using whole genome sequencing for the diagnosis of rare disorders. How it is being carried out and the preliminary results. We will also discuss the next steps in the project.

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Leveraging our common African origins to understand human evolution and health - Ambroise Wolkam

To embrace the prospects of accurately diagnosing thousands of monogenic conditions, predicting disease risks for complex traits or diseases, tailoring treatment to individuals' pharmacogenetic profiles, and potentially curing some diseases, research into African genomic variation is a scientific imperative. African genomes harbor millions of uncaptured variants accumulated over 300,000 years of modern humans' evolutionary history, with successive waves of admixture, migration, and natural selection combining with extensive ecological diversity to create a broad and exceptional genomic complexity. Increased availability of African genomes will improve our understanding of evolutionary history of humans, refine our studies of genomic variation associated with complex traits, and improve how we can leverage knowledge of population-specific variants in health and disease to improve genetic medicine for Africans and potentially in all populations. The extent of novel variants found in within a relatively limited number of African genomes suggests that hundreds of thousands, if not milions, of African genomes still need to be sequenced.

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Expanding studies of global genomic diversity with complete, telomere-to-telomere (T2T) assemblies - Karen Miga

The human reference genome is the most widely used resource in human genetics and is due for a major update. Its current structure is a linear composite of merged haplotypes from more than 20 people, with a single individual comprising most of the sequence. It contains biases and errors within a framework that does not represent global human genomic variation. A high-quality reference with global representation of common variants, including single-nucleotide variants, structural variants and functional elements, is needed. The Human Pangenome Reference Consortium aims to create a more sophisticated and complete human reference genome with a graph-based, telomere-to-telomere representation of global genomic diversity. Here we leverage innovations in technology, study design and global partnerships with the goal of constructing the highest-possible quality human pangenome reference. Our goal is to improve data representation and streamline analyses to enable routine assembly of complete diploid genomes. With attention to ethical frameworks, the human pangenome reference will contain a more accurate and diverse representation of global genomic variation, improve gene–disease association studies across populations, expand the scope of genomics research to the most repetitive and polymorphic regions of the genome, and serve as the ultimate genetic resource for future biomedical research and precision medicine.

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The human genome is finally finished: what have we been missing for the past 20 years? - Adam Phillippy

The Telomere-to-Telomere (T2T) Consortium recently completed the entire sequence of a human genome, introducing over 200 million bases of new sequence and correcting multiple errors in the prior reference. In parallel, the Human Pangenome Reference Consortium (HPRC) released a draft human pangenome reference containing an additional 47 phased, near-complete diploid assemblies from a genetically diverse cohort. This pangenome revealed novel alleles at structurally complex loci and contributed an additional 100 million bases of polymorphic euchromatic sequence. Use of these updated reference sequences was shown to reduce analysis bias and significantly increase the number of variants identified compared to the GRCh38 reference. This added genomic information provides opportunities for new variational and functional studies and is expected to advance our understanding of human genomics and disease.

As one example, the short arms of the human acrocentric chromosomes 13, 14, 15, 21, and 22 have been understudied due to their omission from prior human reference genomes. Our initial analysis of these chromosome arms in the context of the pangenome has revealed the presence of pseudo-homologous regions (PHRs) indicative of recombination between non-homologs. The PHRs include sequences previously shown to lie at the breakpoint of Robertsonian translocations, and their arrangement is compatible with crossover in inverted duplications on chromosomes 13, 14, and 21. The ubiquity of signals of recombination between heterologous chromosomes seen in the HPRC draft pangenome’s acrocentric assemblies suggests that these shared sequences form the basis for recurrent Robertsonian translocations, providing sequence and population-based confirmation of hypotheses first developed cytogenetically fifty years ago.

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Integrated single-cell epigenomics and transcriptomics of the childhood brain

Single-cell genomics enables sequencing of individual cells in complex tissues, thereby allowing the identification of cell type populations in heterogeneous tissues. In this project, we are assembling a comprehensive cell atlas of the childhood brain by performing joint chromatin and transcriptome profiling at the single-cell resolution of healthy tissues from five brain regions and seven donors. In addition, we are profiling donors diagnosed with focal cortical dysplasias, a major cause of epilepsy in children. The obtained cell atlas resource, combining single-cell ATAC-seq (scATAC-seq) and single-nuclei RNA-seq (snRNA-seq) performed from the same cell, will be used to study cell populations and regulatory networks in neuronal development in the early stages of life. Furthermore, it will help determine the epigenetic and transcriptomic changes between the childhood and matured adult brain. This resource will be open to the entire research community through the Human Cell Atlas, addressing two unmet needs: a lack of reference for the childhood brain and a lack of representation of the admixed Brazilian genetic background in current references. The resource will be significant for studying the early stages of brain development and brain-related diseases affecting children.

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Discussing genomic data sharing in Latin America: The Brazilian initiative on Precision Medicine (BIPMed) and the Latin-American Databases of Genetic Variation (LatinGen) - Iscia Lopes-Cendes

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Genes, Rights, Freedoms & Duties: an Approach to Bioethical Dilemmas in Pediatrics - María Susana Ciruzzi

Let's imagine the following scenario: our patient, Jay, 4 years old, must undergo a tumour resection (osteosarcoma). The surgery is a success, Jay recovers and after a couple of years without recurrence he is declared tumour free. The extracted tissue is stored in the hospital tumour bank.

Years go by and:

1. Jay suspects that he is the son of the disappeared person. DNA can be extracted from the stored tissue for comparison with the samples stored in the National Genetic Data Bank. So he’s human right to identity could be granted.
2. Jay, now an adult, refuses to recognize his son and to provide a blood sample to determine the DNA profile and compare it. The child's mother requests the sample from the tumour bank. So the human right to identity of his son could be granted.
3. Jay, as an adult, followed the bad path of bad company. He participates in a crime where a person dies. The police find a cigarette butt at the crime scene, they have had their sights on him for a long time, and ask to compare that sample with the tissue stored in the tumour bank, so that the bad guy (Jay) could be caught.
4. Jay is a correct citizen and respectful of the rules. But a paternal uncle has a hard time. He apparently committed a crime and the police request access to the sample stored in the tumour bank to be able to compare it with the genetic fingerprints detected at the crime scene, so that the bad guy (who is not Jay) could be caught.
5. Jay is a 3 yo kid. His parents are afraid that he could carry a Hunttington Disease gene and they want him to be tested to prevent or reduce future harm.
6. Jay is a 3 yo that needs a bone marrow transplant. His parents are thinking of having another baby in order to fine a perfect bone marrow donor match.

6 scenarios…should we have different legal and bioethical approaches?

Concerns about confidentiality, trust, autonomy, open future, parental responsibility, and justice arise as well in all these 6 scenarios.

It is essential that the issue is not solely discussed from a legal perspective, but also from a bioethicsl one, as medical professionals and institutions might be directly confronted with these issues. Also, ethics guidance might influence policy decisions, and ultimately legislation.

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Human genetic diversity alters off-target outcomes of therapeutic gene editing - Luca Pinello

CRISPR gene editing holds great promise to modify DNA sequences in somatic cells to treat disease. However, standard computational and biochemical methods to predict off-target potential focus on reference genomes. We developed an efficient tool called CRISPRme that considers single-nucleotide polymorphism (SNP) and indel genetic variants to nominate and prioritize off-target sites. We tested the software with a BCL11A enhancer targeting guide RNA (gRNA) showing promise in clinical trials for sickle cell disease and ?-thalassemia and found that the top candidate off-target is produced by an allele common in African-ancestry populations (MAF 4.5%) that introduces a protospacer adjacent motif (PAM) sequence. We validated that SpCas9 generates strictly allele-specific indels and pericentric inversions in CD34+ hematopoietic stem and progenitor cells (HSPCs), although high-fidelity Cas9 mitigates this off-target. This report illustrates how genetic variants should be considered as modifiers of gene editing outcomes. We expect that variant-aware off-target assessment will become integral to therapeutic genome editing evaluation and provide a powerful approach for comprehensive off-target nomination.

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Population genomic diversity in the health of the amazon region - Andrea Ribeiro dos Santos

The genomic characterization of urban and traditional populations (African and Native American), and it’s application to improve in public health policies remains as one of the most challenging concerns nowadays. It is even a greater concern for populations with lower representation in major public databases available.

BRAZIL is one of the most admixed countries in the world, build from of different ethnic groups: Native Americans, Europeans, Africans, Asians and the Middle East, at different times in history. Migratory processes produced stratified contribution among the five regions of the country. The population of the AMAZON is a highly diverse genetically with important contribution of SPECIFIC AND RARE ALLELES. But very little is known about the genomic diversity of this region, therefore, investigating the individual and/or population genetic variability by WGS, can help in the prevention and resolution of many health issues in this region.

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Challenges for prediction of complex traits in Chileans based on genetic associations from other populations - Ricardo Verdugo

Human population diversity is often neglected when health care decisions are generalized based on knowledge derived from a handful of populations. Hispanics or Latin Americans account for 0.33% of participants in GWAS, the least represented group worldwide. Our objective was to evaluate how well genetic associations from other populations translate to individuals of admixed ancestry in Latin America. We will present the results of three projects, ChileGenomico, MAUCO, and C19-GenoNet, which recruited and genotyped a total of 8000 participants in Chile. We have tested predictive performance of polygenic risk scores based on associations found in other populations, mainly European, and tested for potential interaction with ancestry and the environment. Performance for eight non-transmissible diseases and for COVID-19 traits was assessed. Replication of associations varied among diseases and ancestry was generally more predictive than PRSs. We detected a significant interaction between a T2D-PRS and intake of sugar-sweetened beverages of fasting glucose, representing the first report of a genetic-by-environment interaction for this trait in Latin Americans. We conclude that PRS must be validated in local populations before implementation and that ancestry must be accounted for to increase accuracy.

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Equity and Genetic Counselling for Rare Diseases in the Brazilian National Health System (SUS). A Model Based in the National Reference for Rare Diseases - Juan Llerena Junior

Can we offer a medical genetic consultation to everyone with a rare disease in Brazil?

Equity and access to medical health in a continental country as Brazil is possible and has pioneered the field of Rare Diseases (RD) shaping a new health provider modality within the Brazilian National Health System (SUS); whereas, an individual with a rare disease can be referred to a Reference Centers for Rare Diseases (RCRD) (23 in the country until this date). Access to diagnostic genetic plataforms, including Inborn Errors of Metabolism/CGH-array/NGS investigation, may be possible due to finantial compensation related to patients registered. Reinbursment per patient assisted may compensate the lack of opportunities and/or access to private health insurance in the country. 80-85% of diagnosis among rare disease may have a monogenic or genetic background making Genetic Counselling a necessary medical expertise found in the RCRD.

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Exome sequencing of Native Americans reveals occupation patterns of South America - Andre Mauricio Ribeiro dos Santos

Studies on the peopling of South America have been limited by the paucity of sequence data from Native Americans, especially from the east part of the Amazon region. We investigated exomic variants of Native American individuals from the Amazon region to draw insights into the ocupation of South America. Using sequence we generated and public available data, we confirm a strong genetic distinction between Andean and Amazonian populations. Our analysis support a occupation scenario from both Pacific and Atlantic coasts.

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Indigenous Ancestry and Admixture in the Uruguayan Population - Lucia Spangenberg

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Population medical genomics in underrepresented ancestries from Latin America and the Pacific - Andres Moreno-Estrada

Genetic data is transforming our understanding of human diversity and disease risk. Latin America is among the regions that concentrate most of the biodiversity of the planet, including the ethnic, linguistic, and cultural diversity of Latin American ancestries. However, despite the globalization of biotechnologies to analyze the human genome, indigenous populations from the Americas remain underrepresented in large-scale genomic studies. In this talk, I will discuss recent efforts to characterize the genetic profile of Indigenous Americans throughout the continent, including regional approaches across Mexico, South America, and the Pacific, as well as ongoing biobanking efforts in these regions. This topic poses challenges and opportunities to adequately study human diversity and its implications in health care. Genomic research should promote the inclusion of underrepresented ancestries while ensuring a framework of respect and culturally appropriate engagement with participant communities so that the benefits from precision medicine are truly global and equitable.