Computer-implemented methods and systems for performing a local assembly of a genomic region of interest include the de novo or assisted creation of a directed graph, such as a directed acyclic graph (DAG), from a plurality of obtained nucleotide sequence reads. First and second sequence reads are aligned to each other to define at least one node of the DAG. Successive alignments of the remaining sequence reads to the then-defined DAG are performed to extend nodes and/or add nodes to the DAG. Graph-aware alignment techniques that produce alignment scores or indicators are employed in defining the nodes of the DAG from the sequence reads. The created DAG represents and describes in detail the genomic region of interest and can be used to perform variant calls.