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Sarah A Slavoff

Publications and source records attributed to Sarah A Slavoff.

4 recordsLinked to original sources
PubMed2026

Expanding the human proteome with microproteins and peptideins.

A major scientific drive is to characterize the protein-coding genome, which is a primary basis for studying human health. But the fundamental question remains of what has been missed in previous analyses. Over the past decade, the translation of non-canonical open reading frames (ncORFs) has been observed across human cell types and disease states1-3, with major implications for biomedical science. However, a key gap in knowledge has been which ncORFs produce small microproteins or alternative protein molecules that contribute to the human proteome. Here we report the collaborative efforts of the TransCODE Consortium4 to produce a consensus landscape of protein-level evidence for ncORFs. We show that about 25% of a set of 7,264 ncORFs gives rise to detectable peptides in a large-scale analysis of 95,520 proteomics experiments. We develop an annotation framework for ncORF-encoded microproteins as human proteins and codify the new conceptual model of 'peptideins' as microproteins that have indeterminate potential as functional proteins. To probe the biological implications of peptideins, we create an evolutionary analysis approach, termed ORF relative branch length (ORBL), and determine that evolutionary constraint is common and associates with observation of ncORF-derived peptides. We then characterize a pan-essential cellular phenotype for one peptidein from the OLMALINC long non-coding RNA. Overall, we generate public research tools supported by GENCODE and PeptideAtlas and advance biomedical discovery for understudied components of the human proteome.

Humans↗
PubMed2025

High-quality peptide evidence for annotating non-canonical open reading frames as human proteins.

A major scientific drive is to characterize the protein-coding genome as it provides the primary basis for the study of human health. But the fundamental question remains: what has been missed in prior genomic analyses? Over the past decade, the translation of non-canonical open reading frames (ncORFs) has been observed across human cell types and disease states, with major implications for proteomics, genomics, and clinical science. However, the impact of ncORFs has been limited by the absence of a large-scale understanding of their contribution to the human proteome. Here, we report the collaborative efforts of stakeholders in proteomics, immunopeptidomics, Ribo-seq ORF discovery, and gene annotation, to produce a consensus landscape of protein-level evidence for ncORFs. We show that at least 25% of a set of 7,264 ncORFs give rise to translated gene products, yielding over 3,000 peptides in a pan-proteome analysis encompassing 3.8 billion mass spectra from 95,520 experiments. With these data, we developed an annotation framework for ncORFs and created public tools for researchers through GENCODE and PeptideAtlas. This work will provide a platform to advance ncORF-derived proteins in biomedical discovery and, beyond humans, diverse animals and plants where ncORFs are similarly observed.

GENCODE↗
PubMed2025

Cellular function of the GndA microprotein during heat shock.

Over the past 15 years, hundreds of previously undiscovered bacterial small open reading frames (sORFs) encoding microproteins of fewer than fifty amino acids have been identified. Biological functions have been ascribed to an increasing number of microproteins from intergenic regions and small RNAs, and many play integral roles in bacterial stress responses. However, despite numbering in the dozens in Escherichia coli, and hundreds in humans, same-strand frameshifted sORFs that internally overlap protein coding sequences remain understudied. To provide insight into nested genes, we characterized GndA, a frameshifted 36-amino acid microprotein nested within the 6-phosphogluconate dehydrogenase (6PGD) coding sequence. Using precise genome editing, we demonstrate independent contributions of GndA and 6PGD to cell growth at high temperature. GndA associates with membrane-associated complexes associated with electron transport and ATP generation, and supports ATP homeostasis during heat shock. Functional characterization of GndA thus adds to the catalog of bacterial microproteins that function in stress responses, while providing clear genetic evidence for the importance of an overlapping gene to cellular fitness.

6PGD↗